Original Paper

Received: June 17, 2013

Accepted after revision: December 31, 2013
Published online: February 26, 2014

Neonatology 2014;105:290296
DOI: 10.1159/000358267

A Double-Blind Randomised Controlled Trial

of Fish Oil-Based versus Soy-Based Lipid
Preparations in the Treatment of Infants with
Parenteral Nutrition-Associated Cholestasis
HughS.Lam a YukH.Tam b TerenceC.W.Poon a HonM.Cheung a
XintingYu a BrendaP.L.Chan c KimH.Lee b BenjaminS.C.Lee c PakC.Ng a

Department of Paediatrics and b Division of Paediatric Surgery, Department of Surgery, The Chinese University of
Hong Kong, and c Department of Pharmacy, Prince of Wales Hospital, Sha Tin, Hong Kong

Abstract
Background: Infants receiving prolonged parenteral nutrition (PN) are at risk of PN-associated cholestasis (PNAC). This
can progress to hepatic failure and death if PN cannot be
discontinued. Fish oil-based parenteral lipid preparation
(FOLP) has been shown to be beneficial in case studies. Objectives: (1) To evaluate whether FOLP could halt or reverse
the progression of PNAC compared with soy-based parenteral lipid preparation (SLP) and (2) to assess the effects of
FOLP on liver function and physical growth. Methods:
Design: double-blind randomised controlled trial. Setting:
level III neonatal intensive care unit. Participants: infants
with PNAC (plasma-conjugated bilirubin concentration
34 mol/l or 2 mg/dl) expected to be PN-dependent for
>2weeks. Intervention: to receive either FOLP or SLP at 1.5
g/kg/day. Primary outcome measure: reversal of PNAC within 4 months after commencement of lipid treatment; secondary outcomes: rate of change of weekly liver function
tests, infant growth parameters, blood lipid profile and episodes of late-onset sepsis. Results: A total of 9 infants were

2014 S. Karger AG, Basel

16617800/14/10540290$39.50/0
E-Mail karger@karger.com
www.karger.com/neo

randomised to the FOLP group and 7 to the SLP group. There

was no significant difference in reversal of PNAC at 4 months
between groups. Rates of increase of plasma-conjugated bilirubin and alanine aminotransferase in the SLP group were
significantly greater than the FOLP group (13.5 vs. 0.6 mol/l
per week and 9.1 vs. 1.1 IU/l per week, respectively, p= 0.03).
Increased enteral nutrition was associated with significant
improvement of PNAC in infants receiving FOLP compared
with SLP (8.5 vs. 1.6 mol/l per 10% increase in enteral nutrition, respectively). The study was terminated prematurely.
Conclusions: progression of PNAC in PN-dependent infants
can be halted by replacing SLP with FOLP and reversed by
increasing the proportion of enteral nutrition in infants receiving FOLP. Replacement of SLP with FOLP in PN-dependent infants who develop PNAC may be considered.
2014 S. Karger AG, Basel

Introduction

Advances in neonatal intensive care [1] have reduced

morbidity and mortality of infants with short bowel syndrome and intestinal failure. These infants often remain

Both H.S.L. and P.C.N. contributed equally to this project.

Professor Pak C. Ng, Professor of Paediatrics

Department of Paediatrics, The Chinese University of Hong Kong
6/F Clinical Sciences Building, Prince of Wales Hospital
Sha Tin, New Territories (Hong Kong)
E-Mail pakcheungng@cuhk.edu.hk

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Key Words
Fish oil-based lipid preparation Newborn infants
Parenteral nutrition-associated cholestasis Randomised
controlled trial

Patients and Methods

This prospective, double-blind, randomised controlled trial
was conducted at a level III university-affiliated neonatal intensive
care unit, one of three tertiary referral centres for neonatal surgery
in Hong Kong. Subjects were recruited within a 38-month period
between May 2008 and June 2011.

fulfilled the inclusion criteria: (1) CBil 34 mol/l (2 mg/dl), (2)

expected to continue requiring PN for >2 weeks and (3) informed
parental consent. The exclusion criteria were: (1) major congenital
or lethal chromosomal abnormalities, (2) multiorgan failure or imminent death and (3) cholestatic jaundice secondary to other
known causes, e.g. congenital or acquired TORCH, syphilis, hepatitis B or C infection, biliary atresia or other intra- or extrahepatic
diseases obstructing bile flow.
Outcome Measures
The primary outcome was reversal of PNAC, defined as CBil
level <34 mol/l within 4 months after commencement of lipid
treatment. The secondary outcomes were rate of change of weekly
liver function tests, infant growth parameters, namely head circumference and body weight, blood lipid profile and number of
episodes of late-onset infection.
Sample Size Calculation
Recent case series indicated that FOLP could halt or even reverse
PNAC in infants with severe short bowel syndrome continuing to
receive a substantial proportion of nutrition parenterally [68]. In
view of the lack of data at commencement of the study, we made the
following assumption: PNAC would resolve in 40% of infants in the
SLP arm and 80% of those in the FOLP arm within the study period.
In all, 27 infants would be required in each arm to achieve 80% power and p= 0.05. As evidenced by the case series already published
[68], it is likely that 40% resolution for SLP was an overestimate and
80% resolution for FOLP an underestimate. Thus, an interim analysis was planned after approximately one third of subjects had been
recruited for re-evaluation and adjustment of the final sample size.
Randomisation
Eligible infants were randomly assigned to receive either FOLP
(10% Omegaven; Fresenius-Kabi AG, Bad Homburg v.d.H., Germany)
or SLP (10% Intralipid; Fresenius-Kabi AG, Uppsala, Sweden). Pharmacists not involved in the care of the infants prepared the lipids and
the clinical and research teams were unaware of the randomisation
during the study period (online suppl. appendix 1; for all online suppl. material, see www.karger.com/doi/10.1159/000358267).
Parenteral and Enteral Nutrition Regimes
Infants randomised to the FOLP arm received FOLP starting at
a dose of 0.5 g/kg/day and gradually advanced to the maximum of
1.5 at 0.5 g/kg/day increments every 2 days. Similar regimes have
been safely used in recent case series [68]. Infants receiving SLP
had the quantity of parenteral lipid decreased to 1.5 g/kg/day as a
reduction has been shown to be beneficial to infants with PNAC
[14]. Further, a regime of 1.5 g/kg/day would keep all other PN
components, including the total volume of fluids, the same as before recruitment. This study design could determine whether improvement of PNAC was simply due to lipid dosage reduction or
replacement of SLP by FOLP. Details of our neonatal intensive care
unit enteral feeding regime and laboratory investigations have
been described previously [2] (online suppl. appendix 2).

Subjects
All infants who required PN underwent routine weekly monitoring of liver function, including CBil and ALT. Infants who developed PNAC were eligible for recruitment into the study if they

Clinical Data
Anthropometric parameters were serially documented. Head circumference was measured weekly. Body weight was measured on the
same electronic scale 3 times per week. Other important clinical parameters, in particular sepsis episodes, were meticulously recorded.

Fish Oil-Based Lipid Treatment of

Cholestasis

Neonatology 2014;105:290296
DOI: 10.1159/000358267

291

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dependent on parenteral nutrition (PN) for survival and

growth. However, prolonged PN has been associated with
serious complications, including nutritional deficiencies,
risks secondary to central venous catheters and PN-associated cholestasis (PNAC) [1, 2]. Neonatal PNAC is characterised by intrahepatic cholestasis and liver fibrosis and
in severe cases can result in liver failure, with corresponding derangement in liver function, including raised plasma-conjugated bilirubin (CBil) and alanine aminotransferase (ALT) [3]. Once PNAC is established, reversal can
only be achieved if the infant is weaned off PN and receives the majority of nutrients enterally. Subsequent failure to wean off PN is associated with high mortality [3].
Recent studies suggest that parenteral lipid preparations
play a critical role in the pathogenesis of PNAC [4, 5]. Phytosterols, a group of plant steroid compounds present in
soy- and safflower oil-based parenteral lipid preparations,
have been shown to decrease bile flow in neonatal piglets
[4]. More importantly, a significant reduction or discontinuation of these preparations can lead to improvement
of PNAC in infants receiving prolonged PN [5].
Recent reports show that replacement of standard soybased parenteral lipid preparation (SLP) by fish oil-based
parenteral lipid preparation (FOLP) can lead to reversal of
PNAC [611]. FOLP is rich in omega-3 long-chain polyunsaturated fatty acids (O3LC-PUFA), whereas omega-6
LC-PUFAs (O6LC-PUFA) predominate in SLP [7]. It has
been postulated that exclusive use of FOLP can enhance
anti-inflammatory pathways and ameliorate proinflammatory effects of SLP on the liver [12, 13]. As lipid is necessary to provide essential fatty acids and sufficient energy
for growth, a preparation free of adverse hepatic effects
would revolutionise PNAC management. The primary objective of the study was to evaluate whether FOLP monotherapy could halt or reverse the progression of PNAC in
PN-dependent infants after 4 months of treatment. The
secondary objectives were to assess the effects of FOLP on
rates of change of liver function and physical growth.

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Fig. 1. A flow diagram illustrating the recruitment of eligible infants.

Ethics and Consent

Ethical approval for the study was obtained from the joint The
Chinese University of Hong Kong-New Territories East Cluster
Clinical Research Ethics Committee. Written informed parental
consent was obtained for all cases. This protocol was in compliance
with the Declaration of Helsinki (version 2000) and International
Conference on Harmonization Good Clinical Practice guidelines.
This trial was registered with the World Health Organization
Chinese Clinical Trial Registry: ChiCTR-TRC-09000718.

292

Neonatology 2014;105:290296
DOI: 10.1159/000358267

Results

Clinical Characteristics of Subjects

A total of 9 infants were randomised to the FOLP and
7 to the SLP group (fig.1) by the time the interim analysis
was undertaken. With increasing public awareness of
FOLP [6, 8, 9], parents became unwilling to consent for
randomisation. In view of the interim results, we decided
to terminate the study prematurely and to publish our
data. Clinical characteristics were similar between the two
groups at the time of randomisation and are summarised
in table1. Linear mixed effects modelling demonstrated
that enteral nutrition was stepped up by 8.5 and 8.8% per
week in the SLP and FOLP group, respectively (p= 0.92;
table2).
Clinical Outcomes
There was no difference in primary outcome between
groups as the median age of resolution of cholestasis was
110 (IQR: 82158) versus 137 (IQR: 106150) days for
FOLP and SLP (p= 0.74), respectively, indicating that the
Lam/Tam/Poon/Cheung/Yu/Chan/Lee/
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Statistical Analysis
Fishers exact test, Mann-Whitney U test and Wilcoxon rank
sum test were used to compare proportions and continuous variables between the FOLP and SLP groups where appropriate.
Longitudinal data, including serial liver function tests and growth
parameters, were subjected to linear mixed-effects modelling to assess the average rate of change during the treatment period (online
suppl. appendix 3). Partial correlation was used to assess the association between the proportion of enteral nutrition and ALT or
CBil while removing the effects of confounding variables (i.e. repeated measurements from each case, weeks of follow-up, sex, gestational age, postnatal age and birth weight). All tests were performed with SPSS for Windows (version 17; SPSS Inc., Chicago, Ill.,
USA). The level of significance was set at 5% (2-tailed) for all comparisons. All results were analysed on an intention to treat basis.

Table 1. Clinical characteristics of the study population

Number of patients
Sex (female), n
Gestation, weeks
Birth weight, kg
Inborn, n
1st min Apgar score
5th min Apgar score
Age of development of PNAC, days
Age of recruitment, days
Baseline CBil, mol/l
Baseline ALT, IU/l
Diagnosis leading to prolonged PN, n
NEC
SGIDP
SBS
Minimisation criteria for randomisation, n
Aetiology
Non-inflammatory
Inflammatory
Birth weight
<1,000 g
1,000 g
Use of parenteral lipid prior to recruitment
<3 weeks
3 weeks

FOLP group

SLP group

p value

9
3 (33%)
29 (2834)
1,410 (7702,665)
7 (78%)
7 (3, 8)
8 (7, 9)
38 (2347)
48 (2755)
86 (42163)
29 (2531)

7
3 (43%)
29 (2637)
1,240 (8702,180)
4 (57%)
8 (38)
8 (79)
32 (1158)
41 (3165)
92 (72143)
12 (1280)

0.71
0.96
0.79
0.39
0.91
0.87
0.67
0.92
0.61
0.58

2 (22%)
2 (22%)
5 (56%)

4 (57%)
2 (29%)
1 (14%)

5 (56%)
4 (44%)

3 (43%)
4 (57%)

3 (33%)
6 (67%)

3 (43%)
4 (57%)

3 (33%)
6 (67%)

2 (29%)
5 (71%)

0.27
0.84
0.17

Data are presented as medians (with IQR in parentheses) unless otherwise indicated. NEC= Necrotising enterocolitis; SGIDP= severe gastrointestinal dysmotility of prematurity; SBS= short bowel syndrome.

Changes in CBil and ALT Concentrations over Time

By univariate linear mixed effects modelling, SLP was
found to be positively associated with CBil (p = 0.01),
whereas the proportions of enteral feeding (p = 0.04),
birth weight (p< 0.01) and body weight at the time recruitment (p< 0.01) were negatively associated. Univariate analyses also showed that SLP (p= 0.01), female sex
(p= 0.04) and proportion of enteral feeding (p= 0.05)
were positively associated with ALT. Compared with the
Fish Oil-Based Lipid Treatment of
Cholestasis

null hypothesis (i.e. no change in CBil with time), there

was a significant increase in CBil of 13.5 mol/l per week
in the SLP group (i.e. the rate of increase was significantly different from the null hypothesis, p< 0.01) but not in
the FOLP group (0.6 mol/l per week, p= 0.90; table2;
fig.2). The rate of increase of CBil in the SLP group was
significantly greater than in the FOLP group (p= 0.03;
table2; fig.2). Similarly, ALT significantly worsened, increasing by 9.1 IU/l per week in the SLP group (p< 0.01)
but not in the FOLP group (1.1 IU/l per week, p= 0.71).
The rate of increase of ALT in the SLP group was also significantly greater than in the FOLP group (p= 0.02).
Interaction between Enteral Nutrition, Liver Function
and Parenteral Lipid
We then examined the interaction between various parameters and changes of CBil or ALT concentrations during the treatment period by multivariate linear mixedeffects modelling. The significant factors retained in the
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PNAC of most cases in both groups had resolved by

4months (table2); 3 of the 9 infants in the FOLP group
recovered from PNAC while receiving PN, whilst none in
the SLP group did. There were 2 deaths in the SLP group.
Both died of hepatic and multiorgan failure secondary to
septicaemia. All infants in the FOLP group survived and
were discharged from hospital. There were no significant
differences between clotting and lipid profiles between
groups (table2).

Table 2. Clinical outcomes of study subjects

Number of patients
Rate of increase
CBil, mol/l per week
ALT, IU/l per week
CBil, mol/l per 10% enteral nutritiona
ALT, IU/l per 10% enteral nutritiona
Enteral nutrition, %/week
Weight, g/week
Head circumference, cm/week
Duration of study lipid preparation, days
Age PNAC resolved, days
Sepsis episodes during study period, n
Haemoglobin, g/dl
White cell count
Platelet
Total cholesterol
HDL
LDL
Triglycerides
Deaths before discharge, n

FOLP group
9
0.6 (9.5 to 10.8)
1.1 (5.2 to 7.5)
8.5 (14.6 to 2.3)
3.0 (8.1 to 2.1)
8.8 (2.215.5)
128 (103153)
0.49 (0.370.61)
40 (1890)
110 (82158)
2 (24)
11.0 (10.111.3)
10.7 (8.911.5)
185 (144246)
3.2 (2.94.0)
0.5 (0.50.6)
2.0 (1.92.6)
1.4 (1.31.8)
0 (0%)

SLP group

p values

7
13.5 (5.421.6)
9.1 (4.114.1)
1.6 (6.2 to 5.8)
9.0 (3.314.6)
8.5 (0.816.1)
83 (57110)
0.33 (0.210.46)
74 (2382)
137 (106150)
2 (13)
10.04 (9.2010.80)
12.4 (10.214.1)
179 (118231)
4.3 (3.64.9)
0.6 (0.60.9)
2.8 (2.43.5)
1.8 (1.52.2)
2 (29%)

0.03
0.02
0.05
<0.01
0.92
0.02
0.06
0.75
0.74
0.55
0.11
0.13
0.37
0.27
0.49
0.27
0.17
0.10

Data are presented as medians (with IQR in parentheses) unless otherwise indicated. Rates of increase are
presented as coefficient (with 95% CI in parentheses).
HDL= High-density lipoprotein; LDL= low-density lipoprotein.
aAdjusted for baseline change of the parameter per week.

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by partial correlation analysis. In the FOLP group, increasing proportion of enteral nutrition was significantly
associated with decreasing CBil (r= 0.31, p= 0.02) but
not ALT levels (r= 0.03, p= 0.81). In the SLP group, increasing enteral nutrition was not significantly associated
with any change in CBil (r= 0.05, p= 0.75) but was adversely associated with an increase in ALT (r= 0.47, p=
0.01).
Body Weight and Head Circumference
Body weight increased significantly faster in infants on
FOLP compared with SLP (128 vs. 83 g/week, respectively, p= 0.02). A positive trend was also observed for increase in head circumference (0.49 vs. 0.33 cm/week, respectively, p= 0.06; table2).

Discussion

The primary outcome of PNAC resolution by 4 months

post-treatment was not significantly different between
groups as cholestatic jaundice had already resolved in
most infants by that time. This time point of assessment
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model for explanation of the change of CBil were as follows: (1) baseline change of parameter with time (per
week), (2) choice of lipid preparation and (3) proportion
of enteral feeding. This same set of factors was retained in
the ALT model. After adjusting for baseline changes of
the parameter, increase in enteral nutrition was associated with significant improvement of PNAC in infants
receiving FOLP, with the CBil decreasing by 8.5 mol/l
per 10% increase in enteral nutrition (p< 0.01). In contrast, infants receiving SLP had no such improvement
(decreasing by 1.6 mol/l per 10% increase in enteral nutrition, p= 0.96). In the SLP group, ALT increased by 9.0
IU/l per 10% increase in enteral nutrition (p< 0.01). This
phenomenon, however, was not observed with FOLP
treatment and enteral nutrition (decreasing by 3.0 IU/l
per 10% increase in enteral nutrition, p= 0.24). These results demonstrate that the difference in changes of rate of
improvement of PNAC is dependent on both the choice
of parenteral lipid and the proportion of enteral nutrition. In order to test the robustness of these results, we
also performed partial correlation analysis to assess
whether the same results could be obtained by an alternative statistical technique. The same trends were revealed

Fish Oil-Based Lipid Treatment of

Cholestasis

Neonatology 2014;105:290296
DOI: 10.1159/000358267

Plasma-conjugated bilirubin concentration (mol/l)

SLP group
FOLP group

600
500
400

SLP, mean
(slope = 13.5)

300
200

FOLP, mean
(slope = 0.6)

100
0

10
15
20
Time after recruitment (weeks)

25

Fig. 2. The change in CBil concentrations of study subjects during

the study period. The black solid line represents the best fit line of
the SLP group, and the black dashed lines are 1 SE of the mean.
The grey solid line represents the best fit line of the FOLP group,
and the grey dashed lines are 1 SE of the mean. The slope and
intercept of each linear curve were obtained by linear mixed-effects modelling. The rate of increase of CBil in the SLP group is
significantly higher than in the FOLP group (p= 0.03).

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was only arbitrarily set in the initial study design in the

absence of any pilot data. However, our results did show
that continuous use of SLP was associated with worsening
PNAC and liver damage despite a substantial 50% dose
reduction, whereas there was an arrest in progression
with FOLP. The 4-month time point might have been too
long, such that the PNAC of most infants would have resolved within this period due to discontinuation of PN.
Thus, the more rapid resolution of PNAC in subjects receiving FOLP would not be demonstrated using this time
point of assessment. However, we have shown a difference in progression of PNAC between lipid groups which
may be clinically important. Increasing enteral nutrition
was a critical factor associated with reversal of PNAC in
the FOLP group. In contrast, CBil did not improve with
increasing enteral nutrition in the SLP group during the
study period. Although there was an increase in growth
parameters in both groups, significantly higher rates of
increase in body weight and a positive trend in head circumference were observed in the FOLP group. Thus, our
findings suggest that switching parenteral lipid prepara-

tion from SLP to FOLP in infants with established PNAC

is associated with decreased risk of liver damage and faster rate of recovery from PNAC with increasing proportion of enteral nutrition. It is possible that the worsening
PNAC, despite increased proportion of enteral nutrition
in the SLP group, was due to continuing detrimental effects of even small doses of SLP. This finding supports the
observation that recovery from hepatic dysfunction
would necessitate several weeks of SLP discontinuation
[7] and explains why none of the infants in the SLP group
recovered from PNAC during the study period while receiving PN. More importantly, the design of our study
also demonstrates that the beneficial effects of FOLP are
not simply due to a reduction of dosage in parenteral lipid, as both groups received the same quantity of lipid/kg
per day.
Clinical characteristics, including PNAC severity,
were comparable between groups at recruitment. Beneficial effects demonstrated were statistically and clinically
significant and compatible with previous case series [6
8]. Although recent studies suggested that FOLP may reverse the progression of PNAC [6, 8, 9], we were unable
to demonstrate that prolonged administration of FOLP
without increasing enteral feeding was able to reverse this
process. In a recent report, portal fibrosis associated with
cholestasis persisted despite switching to FOLP [10]. This
observation suggests that the use of FOLP alone could not
completely reverse liver damage associated with prolonged fasting and previous SLP use. In another recently
published case series where a combination of SLP and
FOLP was used, improvement in cholestasis was only
seen in infants after SLP was discontinued [11]. It is plausible that even at low doses, the phytosterols in SLP and
the proinflammatory nature of O6LC-PUFA preparations serve to prevent reversal of PNAC.
Essential fatty acid deficiency has been suggested to
be a potential risk of exclusive use of FOLP in view of its
relatively low levels of O6LC-PUFA [8]. However, a recent cohort study has demonstrated that at 1 g/kg per
day of FOLP, treated infants did not develop biochemical evidence of essential fatty acid deficiency [9]. In addition, almost all patients would be receiving a proportion of nutrition enterally during the study period which
would help further reduce the risk. Thus, as rescue treatment, FOLP monotherapy is likely to be more efficacious than combination therapies in minimizing hepatic
toxicity.
Although the initial study plan was to recruit 27 subjects in each arm, our interim analysis suggested that the
differential effects on cholestasis between the two prepa-

700

rations were much greater than anticipated. It also indicated that, despite gradually increasing enteral nutrition,
those on SLP would not improve at all. Thus, it should be
expected that none of these patients would improve while
receiving SLP. In addition, the magnitude of effects demonstrated in our study is consistent with results of prior
literature and understanding and, importantly, our findings were both statistically and clinically significant. As
more information on FOLP became publically available
since the start of our trial [6, 8, 9], parents in the latter
quarter of the study requested their infants be commenced on FOLP and were unwilling to consent for randomisation. In light of the interim results, and the increasing difficulty in recruitment, we decided to terminate the study and to publish the study results.

Conclusions

This is the first randomised controlled trial to demonstrate that replacement of SLP with FOLP can halt PNAC
progression. The primary outcome of PNAC at 4 months
was not different between groups. However, there was a
significant difference in the rates of change of CBil and
liver function between groups. Gradual improvement in

liver function only occurred in infants receiving FOLP

with increasing enteral nutrition. In contrast, despite increasing enteral nutrition and reducing dosage of SLP by
50%, the hepatic function of SLP infants continued to deteriorate. These findings suggest that even small doses of
SLP can be detrimental, and complete cessation of SLP
and replacement with FOLP may prevent further liver
damage in PN-dependent infants. Future studies should
focus on determining the most appropriate timing of
FOLP treatment and the optimal dosage/regime of FOLP
for treating this life-threatening condition.

Acknowledgements
This project was supported by The Chinese University of Hong
Kong Direct Grant for Research (project codes: 2041480 and
2041528) and a donation from the charity organization Providence Foundation Limited (project code: 6901814). The role of the
funders was purely to provide financial support; funders were not
involved in study design, data analysis or interpretation.

Disclosure Statement
The authors have no conflicting financial or competing interests to declare.

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