Journal of Parenteral and Enteral

Nutrition http://pen.sagepub.com/

Incidence, Prevention, and Treatment of Parenteral Nutrition−Associated Cholestasis and Intestinal

Failure −Associated Liver Disease in Infants and Children: A Systematic Review
Giuseppe Lauriti, Augusto Zani, Roberto Aufieri, Mara Cananzi, Pierluigi Lelli Chiesa, Simon Eaton and Agostino Pierro
JPEN J Parenter Enteral Nutr published online 26 July 2013
DOI: 10.1177/0148607113496280

The online version of this article can be found at:

http://pen.sagepub.com/content/early/2013/07/26/0148607113496280

Published by:

http://www.sagepublications.com

On behalf of:

The American Society for Parenteral & Enteral Nutrition

Additional services and information for Journal of Parenteral and Enteral Nutrition can be found at:

Email Alerts: http://pen.sagepub.com/cgi/alerts

Subscriptions: http://pen.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> OnlineFirst Version of Record - Jul 26, 2013

What is This?

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

496280
research-article2013
PENXXX10.1177/0148607113496280Journal of Parenteral and Enteral NutritionLauriti et al

Article
Journal of Parenteral and Enteral
Nutrition
Incidence, Prevention, and Treatment of Parenteral Volume XX Number X
Month 2013 1­–16
Nutrition–Associated Cholestasis and Intestinal Failure– © 2013 American Society

Associated Liver Disease in Infants and Children: A for Parenteral and Enteral Nutrition
DOI: 10.1177/0148607113496280
Systematic Review jpen.sagepub.com
hosted at
online.sagepub.com

Giuseppe Lauriti, MD, PhD1,2; Augusto Zani, MD, PhD1; Roberto Aufieri, MD1;
Mara Cananzi, MD, PhD1; Pierluigi Lelli Chiesa, MD2; Simon Eaton, BSc, PhD1;
and Agostino Pierro, MD, FRCS(Eng), FRCS(Ed), FAAP3

Abstract
Background: Cholestasis is a significant life-threatening complication in children on parenteral nutrition (PN). Strategies to prevent/
treat PN-associated cholestasis (PNAC) and intestinal failure–associated liver disease (IFALD) have reached moderate success with little
supporting evidence. Aims of this systematic review were (1) to determine the incidence of PNAC/IFALD in children receiving PN for
≥14 days and (2) to review the efficacy of measures to prevent/treat PNAC/IFALD. Methods: Of 4696 abstracts screened, 406 relevant
articles were reviewed, and studies on children with PN ≥14 days and cholestasis (conjugated bilirubin ≥  2 mg/dL) were included.
Analyzed parameters were (1) PNAC/IFALD incidence by decade and by PN length and (2) PNAC/IFALD prevention and treatment
(prospective studies). Results: Twenty-three articles (3280 patients) showed an incidence of 28.2% and 49.8% of PNAC and IFALD,
respectively, with no evident alteration over the last decades. The incidence of PNAC was directly proportional to the length of PN (from
15.7% for PN ≤1 month up to 60.9% for PN ≥2 months; P < .0001). Ten studies on PNAC met inclusion criteria. High or intermediate-
dose of oral erythromycin and aminoacid-free PN with enteral whey protein gained significant benefits in preterm neonates (P < .05, P =
.003, and P < .001, respectively). None of the studies reviewed met inclusion criteria for treatment. Conclusions: The incidence of PNAC/
IFALD in children has no obvious decrease over time. PNAC is directly correlated to the length of PN. Erythromycin and aminoacid-
free PN with enteral whey protein have shown to prevent PNAC in preterm neonates. There is a lack of high-quality prospective studies,
especially on IFALD. (JPEN J Parenter Enteral Nutr. XXXX;XX:XX-XX)

Keywords
parenteral nutrition; intestinal failure; cholestasis; liver disease; child

Background with IF are at risk for IF-associated liver disease (IFALD), the
most relevant and persistent complication in pediatric IF
Parenteral nutrition (PN) provides life-saving artificial nutri-
tion and adequate growth in infants with insufficient intestinal
function due to prematurity and/or major abdominal gastroin- From 1Department of Surgery, UCL Institute of Child Health, London,
testinal surgical procedures. Moreover, PN is especially UK; 2Department of Paediatric Surgery, “G. d’Annunzio” University,
required in infants and children with intestinal failure (IF) Chieti-Pescara, Italy; and 3Division of General and Thoracic Surgery,
caused by a reduced absorptive surface (eg, short bowel syn- Hospital for Sick Children, Toronto, Canada.
drome); an intact, although inefficient, mucosal surface (eg,
Financial disclosures: The study was partly supported by grants from
congenital enterocyte disorders); or an intact mucosal surface the Mittal Research Foundation, London, UK. Agostino Pierro and
with extensive motility dysfunction (eg, chronic intestinal Simon Eaton have been consultants for the development of novel
pseudo-obstructions).1 parenteral amino acids mixtures and have consequently received financial
However, patients on prolonged PN are at risk for a spec- contributions from Fresenius-Kabi.
trum of PN-associated hepatobiliary disorders, ranging from
Received for publication April 23, 2013; accepted for publication June
cholestasis to end-stage liver disease.2 Since its observation in 12, 2013.
early 1970s,3-5 PN-associated cholestasis (PNAC) has more
often been found in preterm neonates and infants, as it occurs Corresponding Author:
Agostino Pierro, MD, FRCS(Eng), FRCS(Ed), FAAP, Hospital for
earlier and hepatic dysfunction can rapidly progress in these Sick Children, 555 University Ave, Suite 1526–First Floor Hill Wing,
patients, therefore remaining one of the most significant com- Toronto, ON M5G 1X8, Canada.
plications of prolonged PN.8 Furthermore, infants and children Email: agostino.pierro@sickkids.ca.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

2 Journal of Parenteral and Enteral Nutrition XX(X)

requiring long-term PN and the most consistent negative prog- meticulous considerations in the prevention and treatment of
nostic indicator for their overall survival.1,7 this disease.24 However, neither a systematic review on studies
Nonetheless, despite advances in the knowledge of bile for- included was done nor a precise definition of PNAC was men-
mation physiology8 and of the molecular basis for neonatal tioned by authors. A recent study systematically reviewed the
cholestasis,9 both PNAC and IFALD are not completely eluci- potential benefits and harms of ω-3 fatty acid lipid emulsions
dated consequences of PN therapy in infants. A multifactorial to prevent complications associated with PN.25 However, the
etiology has been proposed implicating low birth weight, pre- authors included articles with nonhomogeneous characteristic,
maturity, enzyme deficiencies, genetic causes, anatomic fac- such as different initial conditions of patients (eg, prematurity,
tors, susceptibility to cholestatic injury, and factors relevant to patient with IF, and infants with congenital heart disease), dif-
the PN itself.2,7,9-12 A further risk factor is the occurrence of ferent quality of the studies (eg, randomized controlled trial,
severe infections, due to the requirement for central line for RCT, and cohort studies with historical controls), and nonuni-
infusion of PN, and bacterial overgrowth caused by enteral form definition of PNAC and IFALD. Furthermore, an article
starvation and immature immune function.13 by Barclay et al26 reviewed interventions in pediatric IF and its
The prevalence of PNAC and IFALD varies considerably complications (sepsis and IFALD). Although their systematic
among studies, but it is estimated to be approximately 40%- review did include measures taken to prevent or treat cholesta-
60% in infants and up to 85% in neonates who are receiving sis, authors did not mention any definition of IFALD, conse-
long-term PN for IF. Furthermore, the prevalence of the IFALD quently not all the studies included were strictly related to this
is unknown because there is no established definition of liver disease.
disease in this setting and it is unclear whether IFALD should Hence, the aims of our systematic review were (1) to deter-
be diagnosed on the basis of clinical, biological, or histological mine if the incidence of PNAC and IFALD have changed over
criteria.1 time among infants and children receiving PN for ≥ 14 days
Some children who receive long-term PN eventually and if there is a correlation between PNAC, IFALD, and length
develop end-stage liver disease. Although their proportion was of PN; and (2) to evaluate possible methods of prevention and
15% in the 1990s,2 a more recent study suggests that careful treatment of PNAC and IFALD.
management may reduce this to 3%.14 End stage liver disease
has a mortality rate approaching 100% within a year of diagno-
sis if they are unable to be weaned off PN or fail to receive a Materials and Methods
liver and/or intestinal transplant.15,16 Furthermore, small bowel Search Strategy
transplantation is limited by a shortage of organ donors, espe-
cially for premature infants, and by 10 years, patient and intes- A systematic review of the Literature using defined search cri-
tine survival rate is 46% and 29% for intestine-only recipients, teria was performed (Figure 1). Studies published between
and 42% and 39% for combined liver-intestine, respectively.17 1950 and March 2013, using Medline, Embase, and the
Several enhancements in prolonged PN were achieved Cochrane Library were searched. The following search terms
throughout last decades, such as improvements in PN compo- were used: “infant” or “child” or “baby” or “paediatric” or
nents and intensive care measures. Aseptic placement tech- “pediatric” or “neonate” and “parenteral” and “liver” or
niques and strict catheter care have reduced sepsis related to “hepatic” or “hepatitis” or “cholestasis” or “bilirubin.” The
central line catheter.18 Moreover, no significant differences “explode” function and the truncation terms “$” and “*” were
were noticed in the incidence of catheter related-bloodstream used as appropriate to each database to search for all possible
infections in multiple lumen vs single lumen catheters.19,20 variations of the keywords. This search strategy yielded 4696
However, there remains a risk of septicaemia that could be due articles. These 4696 titles and abstracts were screened indepen-
to bacterial translocation.21 dently by 2 authors (GL and RA): Articles not relevant to
In spite of these improvements, preventive strategies for PNAC or IFALD in infants and children were excluded. Of all
both PNAC and IFALD are limited and have reached moderate potentially relevant abstracts, 406 full-text articles were
success, and current therapies for these diseases have little sup- reviewed for the different inclusion criteria. In addition, the
porting evidence in infants.7,22 Even if the most effective treat- same 2 authors screened the references of all full-text articles
ment is advancement to full enteral feeds and discontinuation to identify publications not retrieved by the electronic searches.
of PN, this process is often impossible because of poor intesti- For individual selected studies 2 authors (GL and AZ) indepen-
nal function or inadequate gut length.23 Therefore, PNAC and dently graded the level of evidence (LoE) presented using the
IFALD remain significant life-threatening complications and 1 Oxford Centre for Evidence-Based Medicine “Levels of
of the recognized predictor factors of mortality in infants and Evidence” methodology (Table 1).27
children on long-term PN.22 To obtain homogeneous collection of patients, included
Currently, no systematic reviews are available on incidence articles were divided into 3 groups according to pediatric age
of both PNAC and IFALD in infants and children. An exhaus- or liver disease both in incidence, prevention, and treatment
tive review summarizes current knowledge on PNAC, with analysis (Table 2).

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 3

Table 2.  Subgroups of Studies According to Pediatric Age or

Liver Disease.

Group Definition
1 Studies including exclusively preterm neonates (ELBW
and VLBW), focusing on PNAC
2 Studies on neonates (LBW, at term, or not specified),
infants, and children without IF related disease,
focusing on PNAC;
3 Studies on neonates, infants, and children with IF
entirely focusing on IFALD

ELBW, extremely low birth weight; IF, intestinal failure; IFALD, intes-
tinal failure–associated liver disease; LBW, low birth weight; PNAC, par-
enteral nutrition–associated cholestasis; VLBW, very low birth weight.

review only studies where cholestasis or liver disease were

defined as conjugated bilirubin (CB) ≥ 2 mg/dL (or 34 μmol/L)
in association with a prolonged duration of PN administration
(≥ 14 days, Figure 2), as most episodes of PNAC or IFALD
occur after 2 weeks of PN.2,28,29 Furthermore, we chose CB as a
marker for both PNAC and IFALD as it is the most frequently
used measure in studies of PNAC/IFALD and is clearly related
Figure 1.  Search criteria applied to perform the systematic to the risk of liver failure.6,9-12,15,16,18 In addition, to avoid any
review of the literature. synonymous use of PNAC and IFALD, only articles with an
explicit mention of IF were included in the IFALD group.
Table 1.  The Oxford Centre for Evidence-Based Medicine Patients developing cholestasis for causes unrelated to PN
“Levels of Evidence” Methodology.27 (eg, genetic or metabolic disorders, congenital infections, hae-
molysis, liver dysfunction, or extrahepatic obstructions) were
LoE Prevention or Therapy Study Type excluded from the study. Case reports and case series were
1a SR (with homogeneity) of RCTs excluded: Only articles with ≥ 10 patients were considered in
1b Individual RCT (with narrow confidence interval) our systematic review. Patients older than 18 years were not
1c All or nonea included.
2a SR (with homogeneity) of cohort studies
2b Individual cohort study (including low quality RCT)
Prevention
2c “Outcomes” research; ecological studies
3a SR (with homogeneity) of case-control studies To gain stronger evidence for preventative, only prospective
3b Individual case-control study RCT or cohort studies on prevention of PNAC and IFALD in
4 Case-series (and poor quality cohort and case-control infants and children (age < 18 years) were included (LoE 1 and
studies) 2, Table 1). Patients had to receive PN for ≥ 14 days, and not to
5 Expert opinion without explicit critical appraisal, or based have been affected by cholestasis or liver disease (ie, CB had
on physiology, bench research or “first principles”
to be < 2 mg/dL) at the beginning of studies (Figure 2).
LoE, level of evidence; RCT, randomized controlled trial; SR, systematic
review.
a
All patients died before the medical prescription became available, but Treatment
some now survive on it; or when some patients died before the medical
prescription became available, but none now die on it.
Similar to inclusion criteria for prevention, only prospective
RCT or cohort studies on treatment of in infants and children
(age < 18 years) were included (LoE 1 and 2). PNAC and
Incidence of PNAC and IFALD, their prevention, and their IFALD were defined as CB ≥ 2 mg/dL with PN ≥ 14 days
treatment were analyzed (Figure 2). The inclusion criteria for (Figure 2).
these parameters are reported below.

Data Analysis
Incidence
Incidence of cholestasis per decades (from 1970s to 2000s) and
In spite of different definitions of PNAC and IFALD and to gain per length of PN were assessed by chi-square test for trend.
less biases, we determined to include in the present systematic Results showing P < .05 were considered significant. If

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

4 Journal of Parenteral and Enteral Nutrition XX(X)

Figure 2.  Inclusion criteria established to determine incidence, prevention, and treatment of parenteral nutrition–associated cholestasis.
CB, conjugated bilirubin; PN, parenteral nutrition.

methodologically feasible, studies on prevention or treatment directly proportional to the length of PN, with an incidence
were further compared by meta-analysis software (Review varying from 15.7% in patients receiving PN for 14-30 days up
Manager, RevMan version 5.2, Nordic Cochrane Centre, to 60.8% in patients receiving PN for >60 days (Figure 3; P <
Cochrane Collaboration 2012, Copenhagen, Denmark). .0001).
Furthermore, to examine the incidence of PNAC/IFALD
throughout the past 4 decades we considered only those stud-
Results ies10-12,15,30-32,34-40,44-46 with a precise study period mentioned
Incidence (Tables 3a and 3b, Figure 4a). Because of the paucity of studies
included in both Groups 1 and 3, it seemed no achievable to
Twenty-three articles (3280 patients) met the inclusion criteria determine any variation throughout past decades in these sub-
(Tables 3a and 3b).10,11,12,15,28-46 However, 1 study15 reported groups of patients. There appeared to be an alteration in the
only the median (with interquartile range, IQR) duration of incidence of PNAC over time in the Group 2,10,11,34-40 although
PN. it was not possible to compare these data due to the overlap-
The overall incidence of cholestasis coming from all ping periods that the studies were conducted over (Figure 4b).
included studies was 29.9%, considering both PNAC and Similarly, to reduce bias resulting from including studies that
IFALD. Looking at PNAC, the incidence of cholestasis was were conducted over a long period (with underlying improve-
28.2% and, respectively, 25.5% in preterm neonates (Group 1), ment on PN during the study), we examined the incidence of
and 30.6% in neonates at term or not specified, infants, and PNAC in only those studies with a study period ≤ 5
children (Group 2; Table 3a). The incidence of IFALD was years.10,11,34,36-38,40 Again, there was no obvious alteration in the
49.8% in pediatric patients with IF (Group 3; Table 3b). incidence of PNAC over time (Figure 4c).
To reduce biases given by not specified subgroups of pre-
term neonates and different durations of PN, we further ana-
lyzed the studies of Group 2 in relation to the length of PN.
Prevention
Five of the 14 articles included in Group 210,11,37-39 analyzed Ten studies met the inclusion criteria for prevention of the dis-
the relationship between the duration of PN and PNAC (Table ease (Table 5).30,33,43,47-53 None of these articles were related to
4). When possible, patients overlapping with Group 1 (ELBW IFALD. The articles included investigated possible maneuvers
and VLBW) were excluded. The incidence of PNAC was to reduce the incidence of PNAC throughout “choleretic”

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 5

Table 3a.  Studies on the Incidence of Parenteral Nutrition–Associated Cholestasis (PNAC) in Neonates, Infants, and Children
According to Study Period.

PNAC
N Reference Study Period Age of Ptsa Indication for PN Days of PN CB PNAC pts Incidence (%)

Group 1b
1 Slagle TA et al30 1985-1986 ELBW, Prematurity ≥14 ≥2 mg/dL 0/22 0
VLBW
2 Baserga MC et al31 1998-2000 ELBW Prematurity ≥21 ≥2 mg/dL 38/103 37
3 Costa S et al12 1996-2006 ELBW, Prematurity ≥14 ≥2 mg/dL 55/445 12.3
VLBW
4 Christensen RD 2002-2006 ELBW, Prematurity ≥14 ≥2 mg/dL 179/723 24.7
et al11 VLBW,
LBW
5 Duro D et al32 2004-2007 VLBW Prematurity, NEC ≥14 ≥2 mg/dL 87/127 68.5
- Brown MR et al33 n.m. VLBW Prematurity >21 >3 mg/dL 7/12 58

Group 2b
6 Touloukian RJ 1972-1974 Neonates, Surgery ≥14 ≥2 mg/dL 8/19 42.1
et al34 infants
7 Kubota A et al35 1971-1982 Neonates n.m. ≥14 ≥2 mg/dL 44/77 57
8 Vileisis RA et al36 1977-1978 Neonates Prematurity, ≥14 ≥2 mg/dL 11/33 33.3
surgery, RDS
9 Kubota A et al35 1983-1987 Neonates n.m. ≥14 ≥2 mg/dL 22/72 31
10 Beath SV et al37 1988-1992 Neonates Surgery 28 >2.35 mg/dL 27/74 36.5
11 Forchielli ML 1990 Infants Prematurity, ≥14 ≥2 mg/dL 15/70 21.4
et al38 surgery, sepsis,
ECMO
12 Kubota A et al35 1992-1996 Neonates n.m. ≥14 ≥2 mg/dL 31/124 25
13 Wright K et al10 1997-1999 Neonates n.m. ≥21 ≥2 mg/dL 24/141 17
14 Jensen AR et al39 1996-2007 Neonates Gastroschisis ≥21 ≥2 mg/dL 16/71 22.5
15 Christensen RD 2002-2006 LBW, Prematurity, ≥14 ≥2 mg/dL 178/643 27.7
et al11 neonates surgery, ECMO
16 Nehra D et al40 2007-2011 Neonates Surgical ≥21 ≥2 mg/dL 14/32 43.8
gastrointestinal
condition
- Farrell MK et al41 n.m. Infants, n.m. >15 ≥2 mg/dL 6/55 10.9
children
- Puntis JWL et al42 n.m. Neonates Prematurity, NEC, >14 >2.35 mg/dL 9/53 17
PDA, surgery,
abdominal
distension
- Drongowski RA n.m. Neonates n.m. >49 ≥2 mg/dL 17/32 53.1
et al29
- Teitelbaum DH n.m. Neonates n.m. >14 ≥2 mg/dL 9/21 43
et al28
- Fok TF et al43 n.m. Neonates Prematurity, feed >14 >2.94 mg/dL 58/78 74.4
intolerance,
sepsis, NEC,
surgery, others

CB, conjugated bilirubin (expressed in mg/dL); ECMO, extracorporeal membrane oxygenation; ELBW, extremely low birth weight; LBW, low birth
weight; N, numbers of references to be related to Figure 3a (in articles with mentioned study period); NEC, necrotizing enterocolitis; n.m., not men-
tioned; PDA, patent ductus arteriosus; PN, parenteral nutrition; PNAC: parenteral nutrition–associated cholestasis; RDS, respiratory distress syndrome;
VLBW, very low birth weight.
a
Age of patients at the beginning of PN.
b
Group refers to Table 2.

agents,47,48 antibiotic therapy,49-51 and improvement in nutrition “Choleretic” agents. Trying to improve intrahepatic and
intake, enhancing components of PN, such as protein, trace extrahepatic bile flow and biliary sludge, Teitelbaum et al47
elements, or lipids,43,53 and supporting enteral nutrition30,33 or evaluated the effects of cholecystokinin (CCK, 0.04 µg/kg per
PN cycling.52 dose, i.v., every 12 hours for 14 days) on the development of

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

6 Journal of Parenteral and Enteral Nutrition XX(X)

Table 3b.  Studies on the Incidence of Intestinal Failure–Associated Liver Disease (IFALD) in Pediatric Population (Group 3, see Table
2) According to Study Period.
IFALD IFALD
N Reference Study Period Age of Ptsa Indication for PN Days of PN CB Pts Incidence (%)

Group 3: Neonates, infants, and children with IF

17 Quirós-Tejeira RE 1975-2000 Infants, children SBS >90 ≥2 mg/dL 18/78 23

et al44
18 Sondheimer JM 1984-1997 Infants Surgery ≥90 ≥2 mg/dL 28/42 67
et al45
19 Wales PW et al15 1997-2001 Neonates SBS Median 86ddb >2.94 mg/dL 25/40 62.5
20 Köglmeier J et al46 2001-2002 Infants, children Prematurity, >28 ≥2.94 mg/dL 55/93 59.1
surgery, oncology

CB, conjugated bilirubin (expressed in mg/dL); N, numbers of references to be related to Figure 3a; PN, parenteral nutrition; SBS, short bowel syn-
drome.
a
Age of patients at the beginning of PN.
b
PNAC reported after a median of 86 days of PN (interquartile range, IQR, 55-138 days).

Table 4.  Relation Between the Incidence of Parenteral Nutrition–Associated Cholestasis (PNAC) and Duration of Parenteral Nutrition
(PN) Related to Group 2 (see Table 2).

Reference Days of PN PNAC Pts PNAC Incidence (%)

Duration of PN 14-30 days  
Forchielli ML et al38 14 0/9 0
Forchielli ML et al38 15-21 0/19 0
Christensen RD et al11 14-28 55/365 15
Wright K et al10 14-30 5/123 4.1
Forchielli ML et al38 22-28 2/6 33.3
Jensen AR et al39 25 16/71 22.5
Beath SV et al37 28 27/74 36.5
  Duration of PN 30-60 days  
Forchielli ML et al38 29-42 2/8 25
Christensen RD et al11 29-56 38/77 46
Wright K et al10 31-60 10/68 14.7
Forchielli ML et al38 43-56 0/5 0
Jensen AR et al39 50 35/71 49
  Duration of PN > 60 days  
Wright K et al10 61-90 5/14 35.7
Christensen RD et al11 57-100 12/17 71
Forchielli ML et al38 >56 9/14 64.3
Wright K et al10 91-120 3/4 75
Christensen RD et al11 >100 1/1 100
Wright K et al10 121-150 1/1 100

severe PNAC—defined as CB levels of ≥ 5.0 mg/dL—in a with an open-label trial with comparison of concurrently
neonatal population. CCK failed to prevent severe PNAC untreated controls who refused participation. The population
(Table 5). The study was a RCT recruiting initially only included in the study was heterogeneous, including ELBW
severely premature infants (< 1000 g at birth and with an esti- and VLBW on one hand (Group 1), but also neonates with a
mated gestational age of < 28 weeks, Group 1) and afterward birth weight > 1500 g (Group 2). Furthermore, some of the
also surgical neonates (< 30 days of age at the time of enrol- infants treated with TUDCA had been submitted to wide
ment, Group 2). Therefore, we assigned to this study a LoE 2b. intestinal resection. Therefore, results regarding the effects of
The prospective study by Heubi et al48 investigated the TUDCA should be interpreted with caution in infants with
prophylactic effect of tauroursodeoxycholic acid (TUDCA, short bowel syndrome, since the length of remnant ileum is
30 mg/kg/day) in the development of PNAC. As shown in essential to ensure bile acid absorption and thus, possible
Table 5, TUDCA failed to show any effect in preventing effect of TUDCA in such condition. For these reasons, the
PNAC. Because of difficulties in enrolment, authors proceed article was rated at LoE 2b.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 7

any methods of randomization. The study was then rated at

LoE 1b. The meta-analysis on these 2 RCTs (Figure 5) demon-
strated a significant beneficial effect of erythromycin in pre-
venting PNAC (P < .001).
Kubota et al51 explored the preventive effect on PNAC of 2
different concentrations of metronidazole (MNZ, 25 and 50
mg/kg/day) in a surgical neonatal population (Group 2). The
development of PNAC was not reduced by the administration
of MNZ at each concentration (Table 5). Because of the small
number of patients enrolled and the comparison between not
concurrently cases and controls, the study was allocated a LoE
2b. As a result of the low LoE of the study, meta-analysis of
this article was not achievable.

Nutrition intake.  To reduce the incidence of PNAC, in an RCT

by Brown et al33 on VLBW infants (Group 1), the treatment
group received aminoacid-free PN and whey protein enterally
Figure 3.  Incidence of parenteral nutrition–associated
cholestasis (PNAC) was directly proportional to the length of with added premature infant formula, whereas controls
parenteral nutrition (PN) in Group 2, assessed by chi-square test received standard PN with amino acids and enteral premature
for trend: P < .0001. Data are expressed as means. formula. After up to 3 weeks of PN, none of whey group infants
developed PNAC (0/17, 0%), while 7/12 (58%) controls had
PNAC (P < .001; Table 5). The RCT showed some weak point,
Antibiotic therapy.  With regard to antibiotic treatment, 2 dif- as the authors did not mention any methods of randomization
ferent RCTs49,50 focused on the possible prevention of PNAC or describe the use of power calculations that lead to the num-
with erythromycin in VLBW neonates (Group 1). In the first bers recruited and did not state about concurrent administration
one,49 high-dose of oral erythromycin (12.5 mg/kg/dose every of further treatments. Moreover, the number of patients
6 hours for 14 days) significantly lowered the incidence of recruited was too undersized. These possible risks of con-
PNAC in treated neonates (18/91, 20%) in comparison with founding biases lead this study to be assigned a LoE 2b.
controls (37/91, 41%; P = .003, Table 5). Moreover treated Similarly, Slagle et al30 evaluated the potential benefit of
infants achieved full enteral nutrition significantly earlier (P < early low-volume feedings in very low birth weight (VLBW)
.001), the duration of PN was significantly decreased by 10 neonates in an RCT (Table 5). Although neither early-feeding
days (P < .001), and fewer infants receiving erythromycin had infants nor delayed feeding patients developed PNAC, the
2 or more episodes of septicaemia compared with placebo mean serum concentrations of CB for VLBW in the early feed-
patients (P = .03). The RCT was well-constructed, with possi- ing group were slightly lower than those in the delayed feeding
ble low confounding bias given by his duration. It was con- group on day 18 (0.2 ± 0.02 mg/dl vs 0.3 ± 0.05 mg/dl) and day
ducted in 2 phases, during 2 periods, resulting in an overall 29 of life (0.2 ± 0.02 mg/dl vs 0.3 ± 0.05 mg/dl, P < .05; data
length of approximately 8 years. Even if all VLBW infants expressed mean ± SEM). Leaving aside the lack of methodol-
were routinely started on the same PN, we could not assume ogy used for the power calculation, the modest number of
the nonexistence of any further benefit coming from any sort of patients recruited, and the epoch of the study, what it might be
up-to-date protocols or therapies in such long time. However, surprising is that delayed feeding group did not demonstrate
the article was rated at LoE 1b. In the second RCT50 intermedi- any rising in CB after 15 days of total PN (0.3 ± 0.03 mg/dl vs
ate-dose of oral erythromycin (5 mg/kg/dose every 6 hours for 0.3 ± 0.05 mg/dl). Moreover, PN was initiated in all patients on
14 days) significantly lowered the incidence of PNAC in day 3 of life and was increased uniformly over 4 days (until
treated neonates (2/19, 10.5%) in comparison with controls randomization to total PN or early oral feeding), so that we do
(10/26, 38.5%; P < .05, Table 5). Moreover, the number of not have any data about alimentation on day 1 and 2 of life, as
days required to achieve full enteral feeding (P = .01), the well as further concurrent feeding from day 3 to day 7. The
duration of PN (P < .05), and the time required to achieve a article was then rated at LoE 2b.
body weight ≥ 2500 g (P < .05) were significantly shorter in Salvador et al52 compared the incidence of PNAC in VLBW
treated infants. Furthermore, the incidence of necrotizing infants receiving cycle PN (amino acid solution, TrophAmine,
enterocolitis (NEC) ≥ stage IIa after 14 days of treatment was B. Braun Medical, Irvine, CA, over a 20-hour period, a soy-
significantly lower in the erythromycin group (P < .05). The bean-based lipid emulsion, Intralipid 20%, Fresenius Kabi,
RCT was well-constructed, with adequate power calculation of Homburg, Germany, over 18 hours, and dextrose over 24
the sample size, and without significant confounding bias hours) and those receiving continuous PN (TrophAmine over a
within cases and controls, even if the authors did not mention 24-hour period, Intralipid 20% over 18 hours, and dextrose

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

8 Journal of Parenteral and Enteral Nutrition XX(X)

Figure 4.  (a) Included studies on incidence of parenteral nutrition–associated cholestasis (PNAC) or intestinal failure–associated
liver disease (IFALD) with a study period mentioned. *References are related to Tables 3a and 3b. (b) Incidence of PNAC (± 95%
confidential interval) in article with a study period mentioned. (c) Incidence of PNAC (± 95% confidential interval) in article with study
periods ≤ 5 years. (a, b, c) Dots express the average year of study period. Sizes of dots are related to number of patients in the study; see
legend. Horizontal lines delineate the corespective study period. (b, c) Test for trend not possible because of the overlapping periods
that the studies were conducted over.

over 24 hours). However, the incidence of PNAC was similar subsequent surgical procedures, thus omitting potential wide
in the 2 groups (32% and 31%, respectively; P = ns; Table 5). intestinal resection. Furthermore, even if authors included
The RCT was well-constructed, with adequate methods of ran- extreme prematurity neonates with RDS, birth weights were 2.4
domization, without significant confounding bias within cases ± 0.2 kg in LP and 2.7 ± 0.2 kg in HP, with gestational ages of
and controls, even if no power calculation of the sample size 36.0 ± 0.8 and 37.7 ± 0.9 weeks, respectively, thus likely reduc-
has been mentioned. The study was then rated at LoE 1b. ing the numbers of ELBW and VLBW neonates recruited. The
To enhance components of PN, Vileisis et al53 compared in a article was rated at LoE 2b.
RCT the hepatic effects of 2 different parenteral protein intakes, Fok et al43 randomized preterm and at term neonates (Group
a lower protein regimen (LP: 2.3 g/kg/day) and a higher protein 2) to receive either 1 or 0.0182 mmol/kg/d of manganese sup-
regimen (HP: 3.6 g/kg/day) in patients with structural gastroin- plementation in a high-quality RCT (Table 5). Although there
testinal defect, NEC, and extreme prematurity with RDS was no significant difference in the occurrence of PNAC (58/78
(Groups 1 and 2; Table 5). Although the incidence of PNAC in vs 49/82; P = .073), significantly more infants in the high man-
the LP and HP groups were very similar (27% and 33%, respec- ganese group developed severe conjugated hyper-bilirubinaemia,
tively; P = ns), infants randomized to the HP group developed with peak serum CB > 100 mmol/L (5.9 mg/dL) in 32/78
PNAC earlier than the LP group (27 ± 4 vs 47 ± 6 days; P < patients vs 20/82; P = .038. The RCT illustrated well-constructed
.01), and achieved a significantly greater peak of CB (8.4 ± 1.6 methods, even if there were some low risk biases in the high
vs 3.2 ± 0.3 mg/dl; P < .001; data expressed mean ± SEM). manganese group, such as slightly smaller gestational age (31.0
Leaving out the time of the study, the inclusion criteria to recruit ± 3.9 vs 32.0 ± 4.8, respectively; mean ± SD), higher number of
patients were indefinite, as authors did not mention further neonates with NEC (42.3 vs 34.1%), lower days of age when PN
information on the structural gastrointestinal defect, such as on started (5.0 {4.0, 7.0} vs 5.0 {4.0, 8.0}), and more days on PN

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 9

Table 5.  Studies on Prevention of Parenteral Nutrition–Associated Cholestasis (PNAC) in Children.

PNAC in Treated PNAC in Untreated

Reference Groupa Treatment Study Design (ratingb) Pts (incidence %) Pts (incidence %) P Value
Choleretic agents
Teitelbaum DH et al47 1,2 Cholecystokinin (0.04 RCT (2b) 10/114 (9) 13/111 (12) ns
µg/kg/12 hours)
Heubi JE et al48 1,2 Tauroursodeoxycholic Prospective 22/22 (100) 32/32 (100) ns
acid (30 mg/kg/day) nonrandomized (2b)
Antibiotics
Ng PC et al49 1 Erythromycin (12.5 RCT (1b) 18/91 (20) 37/91 (41) .003
mg/
kg/6 hours)
Ng YY et al50 1 Erythromycin (5 mg/ RCT (1b) 2/19 (10.5) 10/26 (38.5) <.05
kg/6 hours)
Kubota A et al51 2 Metronidazole (25 mg/ Prospective 2/9 (22) 4/21 (19) ns
kg/day) nonrandomized (2b)
Kubota A et al51 2 Metronidazole (50 mg/ Prospective 1/12 (8) 4/21 (19) ns
kg/day) nonrandomized (2b)
Nutrition intake
Brown MR et al33 1 Aminoacid-free PN RCT (2b) 0/17 (0) 7/12 (58) <.001
with enteral bovine
whey protein
Slagle TA et al30 1 Early low-volume RCT (2b) 0/18 (0) 0/22 (0) ns
enteral feeding
Salvador A et al52 1 Early PN cycling RCT (1b) 11/34 (32) 11/36 (31) ns
Vileisis RA et al53 1,2 Low (2.5 g/kg/day) vs RCT (2b) 6/22 (27.3) 7/21 (33.3) ns
high protein regimen
(4.0 g/kg/day)
Fok TF et al43 2 Manganese RCT (2b) 58/78 (74.4) 49/82 (59.8) ns
supplementation

ns, not significant; PN, parenteral nutrition; PNAC, parenteral nutrition–associated cholestasis; RCT, randomized controlled trial.
a
Group refers to Table 2.
b
Rating refers to the Oxford Centre for Evidence-Based Medicine “levels of evidence” methodology28 (Table 1).

Figure 5.  Meta-analysis on 2 different doses of erythromycin to prevent parenteral nutrition–associated cholestasis (PNAC). Ery,
erythromycin; QDS, quater die sumendus, 4 times a day.

(41.0 {26.0, 77.3} vs 40.0 {20.5, 67.5}; median {25th and 75th Bad Homburg v.d.h., Germany) to reverse PNAC,54-56 none
percentiles}). Even so, this study was assigned a LoE 1b. have been proper case control/cohort prospective studies since
historical controls were used (LoE 4).
Treatment
Discussion
There were no articles which strictly met our inclusion criteria.
Although there have been several articles on the potential of a There are many complications associated with PN, one of the
fish-oil-based fat emulsion (Omegaven, Fresenius Kabi AG, most common in infancy is PNAC.6 Similarly, IFALD is the

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

10 Journal of Parenteral and Enteral Nutrition XX(X)

most serious complication in patients with IF receiving long- association was first noted by Beale et al58 who showed that the
term PN, and it is the most consistent negative prognostic indi- incidence of cholestasis (defined as CB ≥ 1.5 mg/dL) was 10%
cator for overall survival in these patients.7 after 10 days of PN but increased to 90% in those treated for >3
Nonetheless, many weak points are still present in the lit- months. This correlation could also explain the higher inci-
erature on both PNAC and IFALD. With regard to the defini- dence of IFALD in pediatric IF, because of the longer PN (ie,
tion of cholestasis and liver disease, they are conventionally PN > 28 days, Table 3b). However, because of the paucity of
defined as CB ≥ 2 mg/dL (or 34 μmol/L) in pediatric popula- studies included in Group 3, no further significant subanalysis
tion. Although the cutoff value is considered arbitrary and does were feasible on the incidence of IFALD in patients with long-
not necessarily correlate with any specific hepatic pathology, it term PN.
has been extensively used in pediatric studies.28,46 Furthermore, There has been no obvious decrease in the incidence of both
the definition of PNAC and IFALD are not standardized, even PNAC and IFALD over the last 40 years. Because of the lack
if one of the most commonly definition used is CB ≥ 2 mg/dL of studies exclusively on preterm neonates (Group 1) and on
(or 34 μmol/L) in association with a duration of PN ≥ 14 IFALD (Group 3), we could not achieve any consideration on
days.2,28,29,47 These brought to heterogeneity between different these patients (Figure 4a). With regard to the Group 2, patients
studies in this field. Moreover, to the knowledge of authors, no are heterogeneous in the populations of infants described, both
systematic review has been published on incidence, preven- in terms of patient age and indication for PN (ie, surgical vs
tion, and treatment of PNAC and IFALD. As mentioned, an medical). Furthermore, since most of the study periods are
up-to-date systematic review on ω-3 fatty acid lipid emul- overlapping, no strict decreasing incidence of PNAC was
sions25 included nonhomogeneous articles on both PNAC and reached in this group (Figures 4b and 4c). In addition, it must
IFALD without a definite definition of PNAC and IFALD. be noted that there appeared to be a lack of recent data in inci-
Moreover, a systematic review on pediatric IF26 did not men- dence of both PNAC and IFALD during the second half of past
tion any definition of IFALD. We acknowledge that our a priori decade. Because of this, none of the articles that met our inclu-
definitions (eg, CB, length of time on PN) as inclusion criteria sion criteria used the novel lipids that have seen widespread
for the systematic review may have excluded some relevant introduction over the past 5 years. It remains to be established
articles, but this was necessary to decrease bias and potential whether the use of such lipids could decrease the incidence of
subjective inclusion or exclusion of articles. PNAC.

Incidence Prevention
Despite improvements in surgical procedures, intensive care Even though there have been numerous studies aimed at pre-
unit (ICU) management, involvement of nutrition support venting PNAC or IFALD, many of these were excluded as they
teams, as well as in the composition and mode of delivery of were retrospective case series. There were only a few articles
PN, both the incidence of PNAC and IFALD remain high with in which interventions were prospectively evaluated. Moreover,
special concern in young infants.56 In the present systematic only some of them met our inclusion criteria to define PNAC.
review, only articles with a homogenous definition of cholesta- As a result, no prospective studies on IFALD were included,
sis related to PN and IF were included (Figure 2). because of different (or lack) definition of the disease. There is
The overall incidence of PNAC and IFALD in the studies evidence of beneficial effect of the management by multidisci-
included ranged from 0% to 74.4% (mean 29.9%). Because the plinary teams with pediatric gastroenterology, pediatric sur-
incidence of PNAC could be age-related, with a higher inci- gery, transplant, and immunology.59 Advances such as the
dence in very-low-birth-weight infants, we separated studies introduction of multidisciplinary teams and protocolization, in
on ELBW and VLBW (Group 1) from remaining (Group 2). A addition to specific therapeutic or surgical modulations, have
further group (Group 3) was assessed to articles exclusively improved the outlook for both PNAC and IFALD has changed
focused on IFALD. We did not notice any obvious relationship considerably in the last decade; fewer children undergo intesti-
between age of patient and incidence of PNAC, although only nal transplantation and waitlist mortality for children listed for
a few articles included children (Table 3a). In contrast with intestine transplantation has also decreased.17,60,61
what we expected, preterm neonates in Group 1 demonstrated
a lower incidence of PNAC vs neonates, infants, and children “Choleretic” agents.  None of the 2 included studies on “cho-
in Group 2 (25.5 vs 30.6%, respectively). This result could be leretic” agents to prevent PNAC in Groups 1 and 2 of patients
biased by not specified preterm neonates included in studies of showed a significant benefit to either TUDCA or CCK (Table
Group 2 (eg, Fok et al43 studied neonates with a mean birth 5).47,48 A previous study with lower doses of CCK (0.02 µg/kg
weight of 1347 g). per dose, i.v., every 12 hours for 14 days) failed to prevent
A further bias, given by different length of PN, was eluci- development of PNAC in severe preterm neonates.28 This arti-
dated in the Group 2 (Figure 3): as expected the development cle was excluded because authors compare prospective cases
of PNAC is closely related to the duration of PN. This with a historical cohort of controls (LoE 4).

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 11

Further RCTs on PNAC in Group 262 and Group 163 of pre- significant prevention of PNAC in comparison with controls.33
term neonates demonstrated that ursodeoxycholic acid Even if the study was focused on severe preterm neonates
(UDCA) significantly decreased serum γ-glutamyl transferase (Group 1), we believe that amino acid-free PN would not be
activity (a widely and early sensitive used marker in detecting acceptable for any other than very individualized use, thus
PNAC) during PN, associated with an earlier, albeit not signifi- restricting its employment in those who tolerate early enteral
cant, achievement of full enteral feeding. Both trials were feeds with premature infants formula added with whey
excluded from the systematic review as no definition of cho- protein.
lestasis was included. Even if the first study62 was a high-quality Furthermore, some,67,68 but not all,69,70 studies excluded
RCTs (LoE 1b), the latter63 compared cases to control neonates from this systematic review support early enteral feeding. All
with significantly lower gestational age and birth weight studies but 168 were exclusively on Group 1 neonates and did
(LoE 2b). However, due to these encouraging results, the role not meet the inclusion criteria because of short-term PN67,68,70
of UDCA in preventing PNAC may warrant further or lack of definition of PNAC.69 Moreover, the dated RCT by
investigation. Dunn et al67 demonstrated high risk of biases given by vague
inclusion and exclusion criteria and the small number of neo-
Antibiotic therapy. Intraluminal bacterial overgrowth with nates involved (LoE 2b), and the RCT by Leaf at al68 included
subsequent translocation and sepsis, catheter related sepsis, a slightly higher proportion of infants ≥ 1250 g in the early
and any other conditions that produce a systemic inflammatory group. In addition, all these prevention studies were performed
response, such as NEC, are closely associated with PNAC.64 predominantly or exclusively on severe preterm neonates
Despite this, studies with 2 doses of MNZ prophylaxis in (Group 1),30,33,67,70 and some procedures (ie, early low volume
Group 2 of patients failed to show any benefit (Table 5).51 feeding or aminoacid-free PN with enteral whey proteins) are
In contrast, both high and intermediate-dose of oral erythro- not applicable in older children or in pediatric IF (Groups 2 and
mycin (12.5 mg/kg/dose, and 5 mg/kg/dose every 6 hours for 3). Subsequently, further prospective studies are needed to cor-
14 days, respectively)49,50 were shown to decrease the inci- roborate the benefit of these procedures both in severe preterm
dence of PNAC and septicaemia in 2 RCTs on Group 1 of pre- neonates and in older pediatric patients.
term neonates (Table 5). The meta-analysis on these 2 RCTs Although 2 retrospective articles39,71 on Group 2 of neo-
(Figure 5) corroborates the beneficial effect of erythromycin in nates (LoE 4) demonstrated that cyclic PN may be associated
preventing PNAC (P < .001). However, this effect may be with a decreased incidence or, perhaps, delay in onset of
mediated via the prokinetic effects of erythromycin rather than PNAC, the RCT included on this manoeuvre52 did not reach
its antibiotic effects. Moreover, these results are homogeneous any beneficial effect in cycling PN to prevent PNAC in VLBW.
to the significant evidence that high-doses of erythromycin, This result could be expected as the only difference between
even when administered orally, can reduce the time required by the 2 groups was the length of administration of the amino acid
premature infants with nonobstructive gastrointestinal dys- solution (over 20 hours in the group with cycle PN vs over 24
motility to achieve full enteral nutrition, and thus reduce their hours in those with continuous PN), with presumably the same
dependence on PN. Furthermore, none of the RCTs published final daily amount of the solution in the 2 groups. Moreover,
so far reported any major side effects, in particular, hypertro- the length of administration of the soybean-based lipid emul-
phic infantile pyloric stenosis and life-threatening cardiac dys- sion in both groups was equal (over 18 hours).
rhythmia.65 However, even if oral erythromycin was As well as specific interventions undertaken to prevent
demonstrated to reduce the incidence of PNAC in VLBW, PNAC or IFALD, there may be other ways to reduce its inci-
results obtained in this particular subset of patients could not dence. Sigalet et al72 showed in Group 3 of patients the impor-
be extrapolated in neonates at term or in older group of patients tance of a multidisciplinary team and a protocol-driven strategy
with IF (Groups 2 and 3). Furthermore, uncommon untoward to prevent IFALD. No episode of severe cholestasis (CB > 100
effects, long-term effects on the bowel microflora and the pos- μmol/L for > 2 months) occurred in the cohort of patients fol-
sibility of promoting emergence of multidrug-resistant organ- lowed by the multidisciplinary team in comparison with an
isms in the neonatal ICU, have not been fully evaluated,66 so incidence of 28% in an historical cohort of controls. However,
that oral erythromycin should be used cautiously and selec- because of the presence of the historical cohort of controls, this
tively in preterm infants at higher risk for PNAC. study did not meet our inclusion criteria (LoE 4).
Even if several improvements in components of PN have
Nutritional intake. A way to prevent PNAC is to reach full been achieved throughout last decades, only 2 included articles
enteral feeding and cease PN supplementation. Two RCTs evaluated enhancements in elements of PN.43,53
included in our systematic review on Group 1 preterm neo- In Groups 1 and 2 of patients, Vileisis et al53 demonstrated
nates (Table 5) investigated the use of early enteral feeds to that a LP regimen could be beneficial in reducing incidence of
prevent PNAC in severe preterm neonates.30,33 Both RCTs did PNAC. However, a LP regimen could have an adverse impact
not reach high LoE—2b—and only the study on aminoacid- on growth. Furthermore, the group of infants who presented
free PN with enteral bovine whey protein demonstrated with cholestatic jaundice were exposed to a significantly longer

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

12 Journal of Parenteral and Enteral Nutrition XX(X)

PN and received also a significantly higher glucose supply as may be useful in the prevention on PNAC, in a retrospective
compared with infants without cholestatic jaundice, thus analysis of prospectively collected data on Group 2 of neonates
achieving a LoE 2b. Therefore, the role of aminoacid intake Nasr et al81 have stated that with >80% of PNAC patients being
was hardly assessed. weaned from PN without adverse hepatic sequelae, it is diffi-
In a good-quality RCT (LoE 1b) on Group 1 neonates, Fok cult, in the absence of definitive evidence of efficacy and
et al43 showed that manganese supplementation in excess of safety for Omegaven together with increased costs, to justify
recommendations causes a more severe degree of conjugated its routine use in a low-risk population (such as the surgical
hyperbilirubinaemia. However, most centers use a trace ele- neonates with mild parenteral nutrition–associated liver dys-
ment solution that provides manganese at recommended lev- function examined in the study) outside formal research proto-
els. It is not known whether a further decrease in manganese cols. To this end, there are various RCTs on the use of new lipid
intake could affect cholestasis. emulsions to prevent/treat PNAC or IFALD currently regis-
In the same field, Spencer et al73 observed in post hoc data tered for recruitment. One RCT of Omegaven vs Intralipid in
analysis of a prospective study on Group 2 of infants (LoE 3b) preventing PNAC in Group 2 of infants with IF is currently
that taurine supplementation did offer a very significant degree completed albeit not published.82
of protection against PNAC compared with no taurine.
However, as infant PN amino acid solutions now contain tau-
Treatment
rine, whether there could be any benefit of increased taurine
supplementation is unknown. Currently there is no truly effective pharmacologic manage-
Even if glutamine supplementation during PN did not ment of both PNAC and IFALD. Maneuvers to treat these dis-
reduce the incidence of sepsis in Group 2 of infants with surgi- eases are limited (bile acid-binding agents, “choleretics” such
cal gastrointestinal disease,74,75 it is still debated whether its as ursodiol, cycling of PN administration, and limitation of
role in the maintenance and repair of gastrointestinal mucosa trace minerals in PN) and have little supporting evidence in
may prevent PNAC/IFALD by protecting the hepatic function. infants. One RCT of UDCA vs placebo for treating PNAC in
A pilot RCT75 with inadequate sample size (LoE 2b) on Group Group 2 of neonates is currently recruiting participants.83
2 of infants with surgical gastrointestinal disease showed that A prospective study from Cober et al84 demonstrated that an
enteral glutamine supplementation had no apparent effect on intravenous (IV) fat emulsion reduction in PN to 1 g/kg/d 2
the duration of PN, tolerance of enteral feeds, or intestinal times per week in neonates diagnosed with PNAC significantly
absorptive or barrier function. However, a more recent RCT76 decline the total bilirubin levels compared with controls (P <
with insufficient sample size (LoE 2b) on Group 1 of infants .01) and significantly shortened the days on PN (P < .05).
demonstrated that parenteral glutamine supplementation pres- However, because of the presence of the historical cohort of
ents a protective effect on the liver by decreasing the serum controls, this study did not meet our inclusion criteria and
levels of aspartate aminotransferase and total bilirubin (P < reached a low LoE (LoE 4).
.05), even if no significant difference was noticed with regard The novel lipids described above have also been evaluated
to direct bilirubin. High-quality RCT would be required to bet- for their ability to reverse PNAC/IFALD. There is increasing
ter assess the benefit of this maneuver. enthusiasm because of the early reports of success and safety
There were a few articles evaluating the possible beneficial with the use of Omegaven to reverse PNAC/IFALD in infants
effect of other elements of PN which were excluded because and children.54-56,85-92 However, most of these studies were ret-
they were retrospective, in patients on short-term PN, or rospective,85-87,92 prospective with no controls,88-90 or prospec-
because of the lack of a clear definition of PNAC. Among tive with historical cohort of controls,54-56 so that there are no
these, a medium-chain:long-chain triacylglycerol 50:50 mix- current data from high-quality prospective RCTs.89,92 Three
ture demonstrated some potential benefits in an adequate-quality studies from the same authors54-56 compared prospective
RCT (LoE 2b) on Group 2 of patients, excluded because of the groups treated with the fish-oil-based fat emulsion vs historical
lack of definition of PNAC.77 This mixture could warrant fur- cohorts of infants (Group 2) treated with Intralipid (LoE 4).
ther investigation. Patients receiving Omegaven had a significantly higher rever-
A novel lipid emulsion containing a mixture of soybean oil, sal of cholestasis while on PN (P < .0001), also in the study
medium-chain triglycerides, olive oil, and fish oil (SMOFlipid, where the fat doses were identical in both groups.55 One RCT
Fresenius Kabi, Bad Homburg v.d.h., Germany) showed some of Omegaven vs Intralipid minimization for treating severe
benefits in a well-constructed RCT (LoE 1b) on Group 2 PNAC in Group 2 of patients is currently ongoing.93
patients on short-term PN (7-14 days).78 Two RCTs of Furthermore, SMOFlipid, in an excluded good-quality RCT
SMOFlipid vs Intralipid for prevention of PNAC in Group 1 of (LoE 1b), significantly reduced total bilirubin levels compared
infants79 and in Group 2 of infants with IF/SBS80 are currently with Intralipid in infants and children (Group 2) receiving
ongoing. home PN.94 Therefore, despite the promise that alternate lipid
Although early reports of success and safety with the use of strategies may have, at present the use of these novel lipids
Omegaven in reversal of PNAC23,54-56 might suggest that it remains investigational and should be restricted to those with

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 13

severe PNAC/IFALD unless in the context of a RCT examin- multidisciplinary teams to treat patients with or at risk of
ing their safety and efficacy as a preventative strategy.89 PNAC/IFALD has almost certainly improved the outcomes
Among “choleretics,” UDCA was tested in a few stud- and it would be unethical and impossible to design a study ran-
ies,95-99 although only 2 study designs were prospective,95,96 domizing patients to receive or not receive care from such a
and only 1 of them was a case-control study, albeit retrospec- team. Similarly, in Europe at least, where novel lipids were
tive97 (all studies at LoE 4). Thus none of these articles met our initially licensed and already very widely used, it is extremely
inclusion criteria, even if UDCA may warrant further investi- difficult to design an RCT of treatment of established PNAC/
gation as there appeared to be a reversal of cholestasis in all but IFALD where 1 arm would exclusively receive soy-based lip-
1 study.98 Two preliminary reports with no controls evaluated ids. In scenarios such as these prospective or retrospective
the role of CCK in Group 2 of infants with PNAC.100,101 Both studies, despite offering lower levels of evidence, may be the
of them showed that CCK appears to be associated with a best we can hope for. One other possibility for these rare disor-
decline in CB levels, so that cholestasis may be reversed by IV ders is to expand the role of registries. A registry exists for the
CCK in the majority of patients. Other studies not included in STEP procedure, for example, but its effectiveness is limited
our review (inclusion criteria not met) assessed the beneficial by the lack of comparative data (eg, alternative surgical proce-
effects of enteral nutrition together with ursodiol in Group 2 of dures, medical therapy, etc).
infants102 or with more composite intestinal rehabilitation pro-
gram in Group 3 of patients.103,104 Even if none of these articles References
were prospective neither case-control designed (LoE 4), all 1. Kelly DA. Liver complications of pediatric parenteral nutrition: epidemi-
achieved a reduction or reversal of cholestasis, which may ology. Nutrition. 1998;14:153-157.
indicate the importance of an aggressive weaning of PN to 2. Touloukian RJ, Downing SE. Cholestasis associated with long-term par-
enteral hyperalimentation. Arch Surg. 1973;106:58-62.
enteral nutrition in infants with both PNAC or IFALD.
3. Peden VH, Witzleben CL, Skelton MA. Total parenteral nutrition. J
Ultimately, irrigation of the biliary tract may provide bene- Pediatr. 1971;78:180-181.
fits by flushing out unexcreted remnants; a retrospective case- 4. Rager R, Finegold MJ. Cholestasis in immature newborn infants: is paren-
control study (LoE 4) by Wales et al105 suggested that teral alimentation responsible? J Pediatr. 1975;86:264-269.
percutaneous transhepatic transcholecystic cholangiography 5. De Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish
oil monotherapy in the management of patients with parenteral nutrition-
may be effective in Group 2 of surgical neonates with PNAC.
associated liver disease. Arch Surg. 2010;145:547-551.
6. D’Antiga L, Goulet O. Intestinal failure in children: the European view. J
Conclusions Pediatr Gastroenterol Nutr. 2013;56(2):118-126.
7. Soden JS. Clinical assessment of the child with intestinal failure. Semin
The incidence of PNAC is directly correlated to the length of Pediatr Surg. 2010;19:10-19.
8. Emerick KM, Whitington PF. Molecular basis of neonatal cholestasis.
PN. This correlation is corroborated by the higher incidence of
Pediatr Clin North Am. 2002;49:221-235.
IFALD in pediatric IF, because of the longer PN. Despite 9. Carter BA, Shulman RJ. Mechanisms of disease: update on the molecular
improvements in the management of infants and children etiology and fundamentals of parenteral nutrition associated cholestasis.
requiring PN and the control of infections, the incidence of Nat Clin Pract Gastroenterol Hepatol. 2007;4:277-287.
both PNAC and IFALD in children does not appear to have 10. Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Increased
incidence of parenteral nutrition-associated cholestasis with aminosyn PF
decreased over the past 4 decades.
compared to trophamine. J Perinatol. 2003;23:444-450.
There is a lack of high quality prospective study to prevent/ 11. Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK.
treat these diseases, especially on IFALD. The only interven- Identifying patients, on the first day of life, at high-risk of developing par-
tions which have been shown to significantly prevent develop- enteral nutrition-associated liver disease. J Perinatol. 2007;27:284-290.
ment of PNAC are limited to severe preterm neonates. They 12. Costa S, Maggio L, Sindico P, Cota F, De Carolis MP, Romagnoli C.
Preterm small for gestational age infants are not at higher risk for paren-
demonstrated benefits in preventing PNAC given by both high
teral nutrition–associated cholestasis. J Pediatr. 2010;156:575-579.
and intermediate-dose of oral erythromycin49,50 or by an ami- 13. Koletzko B, Goulet O. Fish oil containing lipid emulsion in parenteral
noacid-free PN associated with enteral feeding with premature nutrition-associated cholestatic liver disease. Curr Opin Clin Nutr Metab
infant formula and whey protein.33 However, both maneuvers Care. 2010;13:321-326.
might warrant additional examinations and further prospective 14. Colomb V, Dabbas-Tyan M, Taupin P, et al. Long-term outcome of chil-
dren receiving home parenteral nutrition: a 20-year single-center experi-
studies are mandatory to corroborate these results.
ence in 302 patients. J Pediatr Gastroenterol Nutr. 2007;44:347-353.
Omegaven and SMOFlipid may have benefits in prevention 15. Wales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM.
and/or reversal of PNAC and IFALD, although the evidence Neonatal short bowel syndrome: a cohort study. J Pediatr Surg. 2005;40:
for their use is currently limited. Consequently, there is a 755-762.
requirement for further RCTs to better assess prevention and 16. Lilja HE, Finkel Y, Paulsson M, Lucas S. Prevention and reversal of intes-
tinal failure-associated liver disease in premature infants with short bowel
treatment maneuvers against both PNAC and IFALD in infants
syndrome using intravenous fish oil in combination with omega-6/9 lipid
and children. However, we acknowledge that sometimes per- emulsions. J Pediatr Surg. 2011;46:1361-1367.
forming RCTs is simply impossible, and then we are left with 17. Mazariegos GV, Steffick DE, Horslen S, et al. Intestine transplantation in
lower levels of evidence. For example, the introduction of the United States, 1999-2008. Am J Transplant. 2010;10:1020-1034.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

14 Journal of Parenteral and Enteral Nutrition XX(X)

18. Kelly DA. Intestinal failure–associated liver disease: what do we know 38. Forchielli ML, Gura KM, Sandler R, Lo C. Aminosyn PF or trophamine:
today? Gastroenterology. 2006;130:S70-77. which provides more protection from cholestasis associated with total par-
19. Yoshida J, Ishimaru T, Fujimoto M, Hirata N, Matsubara N, Koyanagi N. enteral nutrition? J Pediatr Gastroenterol Nutr. 1995;21:374-382.
Risk factors for central venous catheter-related bloodstream infection: a 39. Jensen AR, Goldin AB, Koopmeiners JS, Stevens J, Waldhausen JH, Kim
1073-patient study. J Infect Chemother. 2008;14:399-403. SS. The association of cyclic parenteral nutrition and decreased incidence
20. Dezfulian C, Lavelle J, Nallamothu BK, Kaufman SR, Saint S. Rates of of cholestatic liver disease in patients with gastroschisis. J Pediatr Surg.
infection for single-lumen versus multilumen central venous catheters: a 2009;44:183-189.
meta-analysis. Crit Care Med. 2003;31:2385-2390. 40. Nehra D, Fallon EM, Carlson SJ, et al. Provision of a soy-based intrave-
21. Donnell SC, Taylor N, van Saene HK, Magnall VL, Pierro A, Lloyd DA. nous lipid emulsion at 1 g/kg/d does not prevent cholestasis in neonates
Infection rates in surgical neonates and infants receiving parenteral nutri- [published online ahead of print July 5, 2012]. JPEN J Parenter Enteral
tion: a five-year prospective study. J Hosp Infect. 2002;52:273-280. Nutr. doi:10.1177/0148607112453072.
22. Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams 41. Farrell MK, Balistreri WF, Suchy FJ. Serum-sulfated lithocholate as an
SA. High rates of mortality and morbidity occur in infants with paren- indicator of cholestasis during parenteral nutrition in infants and children.
teral nutrition–associated cholestasis. JPEN J Parenter Enteral Nutr. JPEN J Parenter Enteral Nutr. 1982;6:30-33.
2010;34:32-37. 42. Puntis JWL, Ball PA, Booth IW. Complications of neonatal parenteral
23. Fallon EM, Le HD, Puder M. Prevention of parenteral nutrition-asso- nutrition. Intensive Ther Clin Monitoring. 1987;8:48-56.
ciated liver disease: role of ω-3 fish oil. Curr Opin Organ Transplant. 43. Fok TF, Chui KK, Cheung R, Ng PC, Cheung KL, Hjelm M. Manganese
2010;15:334-340. intake and cholestatic jaundice in neonates receiving parenteral nutrition:
24. Rangel SJ, Calkinsb CM, Cowlesc RA, et al. Parenteral nutrition–associated a randomized controlled study. Acta Paediatr. 2001;90:1009-1015.
cholestasis: an American Pediatric Surgical Association Outcomes and 44. Quirós-Tejeira RE, Ament ME, Reyen L, et al. Long-term parenteral
Clinical Trials Committee systematic review. J Pediatr Surg. 2012:47, nutritional support and intestinal adaptation in children with short bowel
225-240. syndrome: a 25-year experience. J Pediatr. 2004;145:157-163.
25. Seida JC, Mager DR, Hartling L, Vandermeer B, Turner JM. Parenteral 45. Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholesta-
ω-3 fatty acid lipid emulsions for children with intestinal failure and sis in neonates with intestinal resection and long-term parenteral nutrition.
other conditions: a systematic review. JPEN J Parenter Enteral Nutr. J Pediatr Gastroenterol Nutr. 1998;27:131-137.
2013;37:44-55. 46. Köglmeier J, Day C, Puntis JW. Clinical outcome in patients from a single
26. Barclay AR, Beattie LM, Weaver LT, Wilson DC. Systematic review: region who were dependent on parenteral nutrition for 28 days or more.
medical and nutritional interventions for the management of intestinal fail- Arch Dis Child. 2008;93:300-302.
ure and its resultant complications in children. Aliment Pharmacol Ther. 47. Teitelbaum DH, Tracy TF Jr, Aouthmany MM, Llanos A, Brown MB, Yu
2011;33:175-184. S, et al. Use of cholecystokinin-octapeptide for the prevention of paren-
27. Oxford Centre for Evidence-Based Medicine. Levels of Evidence. March teral nutrition-associated cholestasis. Pediatrics. 2005;115:1332-1340.
2009. Available at: http://www.cebm.net/index.aspx?o=1025. Accessed 48. Heubi JE, Wiechmann DA, Creutzinger V, Setchell KD, Squires R Jr,
March 11, 2013. Couser R, et al. Tauroursodeoxycholic acid (TUDCA) in the preven-
28. Teitelbaum DH, Han-Markey T, Drongowski RA, et al. Use of cholecys- tion of total parenteral nutrition-associated liver disease. J Pediatr.
tokinin to prevent the development of parenteral nutrition-associated cho- 2002;141:237-242.
lestasis. JPEN J Parenter Enteral Nutr. 1997;21:100-103. 49. Ng PC, Lee CH, Wong SPS, et al. High-dose oral erythromycin decreased
29. Drongowski RA, Coran AG. An analysis of factors contributing to the the incidence of parenteral nutrition-associated cholestasis in preterm
development of total parenteral nutrition-induced cholestasis. JPEN J infants. Gastroenterology. 2007;132:1726-1739.
Parenter Enteral Nutr. 1989;13:586-589. 50. Ng YY, Su PH, Chen JY, et al. Efficacy of intermediate-dose oral erythro-
30. Slagle TA, Gross SJ. Effect of early low-volume enteral substrate on mycin on very low birth weight infants with feeding intolerance. Pediatr
subsequent feeding tolerance in very low birth weight infants. J Pediatr. Neonatol. 2012;53:34-40.
1988;113:526-531. 51. Kubota A, Okada A, Imura K, Kawahara H, Nezu R, Kamata S. The effect
31. Baserga MC, Sola A. Intrauterine growth restriction impacts tolerance to of metronidazole on TPN-associated liver dysfunction in neonates. J
total parenteral nutrition in extremely low birth weight infants. J Perinatol. Pediatr Surg. 1990;25:618-621.
2004;24:476-481. 52. Salvador A, Janeczko M, Porat R, Sekhon R, Moewes A, Schutzman D.
32. Duro D, Mitchell PD, Kalish LA, et al. Risk factors for parenteral nutri- Randomized controlled trial of early parenteral nutrition cycling to pre-
tion–associated liver disease following surgical therapy for necrotizing vent cholestasis in very low birth weight infants. J Pediatr. 2012;161:
enterocolitis: A Glaser Pediatric Research Network Study. J Pediatr 229-233.
Gastroenterol Nutr. 2011;52(5):595-600. 53. Vileisis RA, Inwood RJ, Hunt CE. Prospective controlled study of paren-
33. Brown MR, Thunberg BJ, Golub L, Maniscalco WM, Cox C, Shapiro DL. teral nutrition-associated cholestatic jaundice: effect of protein intake. J
Decreased cholestasis with enteral instead of intravenous protein in the Pediatr. 1980;96:893-897.
very low-birth-weight infant. J Pediatr Gastroenterol Nutr. 1989;9:21-27. 54. Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes
34. Touloukian RJ, Seashore JH. Hepatic secretory obstruction with total par- in patients with parenteral nutrition-associated liver injury. Ann Surg.
enteral nutrition in the infant. J Pediatr Surg. 1975;10:353-360. 2009;250:395-402.
35. Kubota A, Yonekura T, Hoki M, et al. Total parenteral nutrition-associ- 55. Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil-based fat
ated intrahepatic cholestasis in infants: 25 years’ experience. J Pediatr emulsion in the treatment of parenteral nutrition-associated liver disease.
Surg. 2000;35:1049-1051. Pediatrics. 2008;121:e678-e686.
36. Vileisis RA, Inwood RJ, Hunt CE. Laboratory monitoring of parenteral 56. Lee SI, Valim C, Johnston P, et al. Impact of fish oil-based lipid emulsion
nutrition-associated hepatic dysfunction in infants. JPEN J Parenter on serum triglyceride, bilirubin, and albumin levels in children with par-
Enteral Nutr. 1981;5:67-69. enteral nutrition-associated liver disease. Pediatr Res. 2009;66:698-703.
37. Beath SV, Davies P, Papadopoulou A, et al. Parenteral nutrition-related 57. Goulet O, Joly F, Corriol O, Colomb-Jung V. Some new insights in intes-
cholestasis in postsurgical neonates: multivariate analysis of risk factors. J tinal failure-associated liver disease. Curr Opin Organ Transplantation.
Pediatr Surg. 1996;31:604-606. 2009;14:256-261.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

Lauriti et al 15

58. Beale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman DV. 80. ClinicalTrials.gov, U.S. National Institutes of Health. Can SMOFlipid®,
Intrahepatic cholestasis associated with parenteral nutrition in premature a Composite Parenteral Nutrition Lipid Emulsion, Prevent Progression
infants. Pediatrics. 1979;64:342-347. of Parenteral Nutrition Associated Liver Disease in Infants? November
59. Sigalet D, Boctor D, Brindle M, Lam V, Robertson M. Elements of suc- 18, 2008. Available at: http://clinicaltrials.gov/ct2/show/NCT00793195.
cessful intestinal rehabilitation. J Pediatr Surg. 2011;46:150-156. Accessed March 8, 2013.
60. Mazariegos GV, Superina R, Rudolph J, et al. Current status of pediatric 81. Nasr A, Diamond IR, de Silva NT, Wales PW. Is the use of parenteral
intestinal failure, rehabilitation, and transplantation: summary of a col- ω-3 lipid emulsions justified in surgical neonates with mild parenteral
loquium. Transplantation. 2011;92:1173-1180. nutrition–associated liver dysfunction? J Pediatr Surg. 2010;45:980-986.
61. Avitzur Y, Grant D. Intestine transplantation in children: update 2010. 82. ClinicalTrials.gov, U.S. National Institutes of Health. Cholestasis
Pediatr Clin North Am. 2010;57:415-431. Prevention: Efficacy of IV Fish Oil. August 6, 2007. Available at: http://
62. Arslanoglu S, Moro GE, Tauschel HD, Boehm G. Ursodeoxycholic acid www.clinicaltrials.gov/ct2/show/NCT00512629. Accessed March 8,
treatment in preterm infants: a pilot study for the prevention of cholestasis 2013.
associated with total parenteral nutrition. J Pediatr Gastroenterol Nutr. 83. ClinicalTrials.gov, U.S. National Institutes of Health. Ursodiol for
2008;46:228-231. Treating Parenteral Nutrition Associated Cholestasis in Neonates.
63. Gokmen T, Oguz SS, Bozdag S, Erdeve O, Uras N, Dilmen U. A con- February 17, 2009. Available at: http://clinicaltrials.gov/ct2/show/
trolled trial of erythromycin and UDCA in premature infants during NCT00846963. Accessed March 8, 2013.
parenteral nutrition in minimizing feeding intolerance and liver function 84. Cober MP, Killu G, Brattain A, Welch KB, Kunisaki SM, Teitelbaum DH.
abnormalities. J Perinatol. 2012;32(2):123-128. Intravenous fat emulsions reduction for patients with parenteral nutrition-
64. Kaufman SS. Prevention of parenteral nutrition-associated liver disease in associated liver disease. J Pediatr. 2012;160:421-427.
children. Pediatr Transplant. 2002;6:37-42. 85. Cheung HM, Lam HS, Tam YH, Lee KH, Ng PC. Rescue treatment of
65. Lam HS, Ng PC. Use of prokinetics in the preterm infant. Curr Opin infants with intestinal failure and parenteral nutrition-associated cholesta-
Pediatr. 2011;23:156-160. sis (PNAC) using a parenteral fish-oil-based lipid. Clin Nutr. 2009;28:209-
66. Ng PC. Use of oral erythromycin for the treatment of gastrointestinal dys- 212.
motility in preterm infants. Neonatology. 2009;95:97-104. 86. Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW. Changing the
67. Dunn L, Hulman S, Weiner J, Kliegman R. Beneficial effects of early paradigm: omegaven for the treatment of liver failure in pediatric short
hypocaloric enteral feeding on neonatal gastrointestinal function: prelimi- bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48:209-215.
nary report of a randomized trial. J Pediatr. 1988;112:622-629. 87. Rollins MD, Scaife ER, Jackson WD, Meyers RL, Mulroy CW, Book LS.
68. Leaf A, Dorling J, Kempley S, et al. Early or delayed enteral feeding Elimination of soybean lipid emulsion in parenteral nutrition and supple-
for preterm growth-restricted infants: a randomized trial. Pediatrics. mentation with enteral fish oil improve cholestasis in infants with short
2012;129:e1260-e1268. bowel syndrome. Nutr Clin Pract. 2010;25:199-204.
69. McClure RJ, Newell SJ. Randomised controlled study of clinical out- 88. Le HD, de Meijer VE, Zurakowski D, Meisel JA, Gura KM, Puder M.
come following trophic feeding. Arch Dis Child Fetal Neonatal Ed. Parenteral fish oil as monotherapy improves lipid profiles in children with
2000;82:F29-F33. parenteral nutrition-associated liver disease. JPEN J Parenter Enteral
70. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA. Nutr. 2010;34:477-484.
Randomised controlled trial of an aggressive nutritional regimen in 89. Diamond IR, de Silva NT, Tomlinson GA, et al. The role of parenteral
sick very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. lipids in the development of advanced intestinal failure-associated liver
1997;77:F4-F11. disease in infants: a multiple-variable analysis. JPEN J Parenter Enteral
71. Takehara H, Hino M, Kameoka K, Komi N. A new method of total paren- Nutr. 2011;35:596-602.
teral nutrition for surgical neonates: it is possible that cyclic TPN prevents 90. Premkumar MH, Carter BA, Hawthorne KM, King K, Abrams SA.
intrahepatic cholestasis. Tokushima J Exp Med. 1990;37:97-102. High rates of resolution of cholestasis in parenteral nutrition-associated
72. Sigalet D, Boctor D, Brindle M, Lam V, Robertson M. Elements of suc- liver disease with fish oil-based lipid emulsion monotherapy. J Pediatr.
cessful intestinal rehabilitation. J Pediatr Surg. 2011;46:150-156. 2013;162(4):793-798.
73. Spencer AU, Yu S, Tracy TF, et al. Parenteral nutrition–associated cho- 91. Le HD, de Meijer VE, Robinson EM, Zurakowski D, Potemkin AK,
lestasis in neonates: multivariate analysis of the potential protective effect Arsenault DA. Parenteral fish-oil-based lipid emulsion improves fatty acid
of taurine. JPEN J Parenter Enteral Nutr. 2005;29:337-344. profiles and lipids in parenteral nutrition-dependent children. Am J Clin
74. Ong EG, Eaton S, Wade AM, et al. Randomized clinical trial of gluta- Nutr. 2011;94(3):749-758.
mine-supplemented versus standard parenteral nutrition in infants with 92. Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams
surgical gastrointestinal disease. Br J Surg. 2012;99:929-938. SA. High rates of mortality and morbidity occur in infants with paren-
75. Duggan C, Stark AR, Auestad N, Collier S, Fulhan J, Gura K. Glutamine teral nutrition associated cholestasis. JPEN J Parenter Enteral Nutr.
supplementation in infants with gastrointestinal disease: a randomized, 2010;34:32-37.
placebo-controlled pilot trial. Nutrition. 2004;20:752-756. 93. ClinicalTrials.gov, U.S. National Institutes of Health. Minimization of
76. Wang Y, Tao YX, Cai W, Tang QY, Feng Y, Wu J. Protective effect IntraLipid Versus Omegaven. November 23, 2010. Available at: http://
of parenteral glutamine supplementation on hepatic function in very clinicaltrials.gov/ct2/show/NCT01247012. Accessed March 8, 2013.
low birth weight infants. Clin Nutr. 2010;29(3):307-311. doi:10.1016/j. 94. Goulet O, Antébi H, Wolf C, et al. A new intravenous fat emulsion con-
clnu.2010.03.009. taining soybean oil, medium-chain triglycerides, olive oil, and fish oil:
77. Lai H, Chen W. Effects of medium-chain and long-chain triacylglycerols a single-center, double-blind randomized study on efficacy and safety in
in pediatric surgical patients. Nutrition. 2000;16:401-406. pediatric patients receiving home parenteral nutrition. JPEN J Parenter
78. Tomsits E, Pataki M, Tölgyesi A, Fekete G, Rischak K, Szollár L. Safety Enteral Nutr. 2010;34:485-495.
and efficacy of a lipid emulsion containing a mixture of soybean oil, 95. De Marco G, Sordino D, Bruzzese E, et al. Early treatment with urso-
medium-chain triglycerides, olive oil, and fish oil: a randomised, double- deoxycholic acid for cholestasis in children on parenteral nutrition
blind clinical trial in premature infants requiring parenteral nutrition. J because of primary intestinal failure. Aliment Pharmacol Ther. 2006;24:
Pediatr Gastroenterol Nutr. 2010;51:514-521. 387-394.
79. ClinicalTrials.gov, U.S. National Institutes of Health. Preventing 96. Spagnuolo MI, Iorio R, Vegnente A, Guarino A. Ursodeoxycholic acid for
Cholestasis Using SMOFLipid®. April 16, 2012. Available at: http:// treatment of cholestasis in children on long-term total parenteral nutrition:
clinicaltrials.gov/ct2/show/NCT01585935. Accessed March 8, 2013. a pilot study. Gastroenterology. 1996;111:716-719.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013

16 Journal of Parenteral and Enteral Nutrition XX(X)

97. Al-Hathlol K, Al-Madani A, Al-Saif S, Abulaimoun B, Al-Tawil K, nous cholecystokinin: a preliminary report. J Pediatr Surg. 1995;30:
El-Demerdash A. Ursodeoxycholic acid therapy for intractable total par- 827-830.
enteral nutrition-associated cholestasis in surgical very low birth weight 102. Javid PJ, Collier S, Richardson D, et al. The role of enteral nutrition in the
infants. Singapore Med J. 2006;47:147-151. reversal of parenteral nutrition-associated liver dysfunction in infants. J
98. Levine A, Maayan A, Shamir R, Dinari G, Sulkes J, Sirotta L. Parenteral Pediatr Surg. 2005;40:1015-1018.
nutrition-associated cholestasis in preterm neonates: evaluation of ursode- 103. Cowles RA, Ventura KA, Martinez M, et al. Reversal of intestinal failure-
oxycholic acid treatment. J Pediatr Endocrinol Metab. 1999;12:549-553. associated liver disease in infants and children on parenteral nutrition:
99. Chen CY, Tsao PN, Chen HL, Chou HC, Hsieh WS, Chang MH. experience with 93 patients at a referral center for intestinal rehabilitation.
Ursodeoxycholic acid (UDCA) therapy in very-low-birth-weight infants J Pediatr Surg. 2010;45:84-87.
with parenteral nutrition-associated cholestasis. J Pediatr. 2004;145: 104. Torres C, Sudan D, Vanderhoof J, et al. Role of an intestinal rehabili-
317-321. tation program in the treatment of advanced intestinal failure. J Pediatr
100. Teitelbaum DH, Han-Markey T, Schumacher RE. Treatment of paren- Gastroenterol Nutr. 2007;45:204-212.
teral nutrition-associated cholestasis with cholecystokinin-octapeptide. J 105. Wales PW, Brindle M, Sauer CJ, Patel S, de Silva N, Chait P. Percutaneous
Pediatr Surg. 1995;30:1082-1085. cholangiography for the treatment of parenteral nutrition-associated cho-
101. Rintala RJ, Lindahl H, Pohjavuori M. Total parenteral nutrition-asso- lestasis in surgical neonates: preliminary experience. J Pediatr Surg.
ciated cholestasis in surgical neonates may be reversed by intrave- 2007;42:1913-1918.

Downloaded from pen.sagepub.com at SYRACUSE UNIV LIBRARY on November 23, 2013