-
http://pen.sagepub.com/Nutrition
Journal of Parenteral and Enteral
http://pen.sagepub.com/content/early/2013/07/26/0148607113496280The
online version of this article can be found at:
DOI: 10.1177/0148607113496280
published online 26 July 2013JPEN J Parenter Enteral
NutrGiuseppe Lauriti, Augusto Zani, Roberto Aufieri, Mara Cananzi,
Pierluigi Lelli Chiesa, Simon Eaton and Agostino Pierro
Associated Liver Disease in Infants and Children: A Systematic
ReviewFailureAssociated Cholestasis and IntestinalIncidence,
Prevention, and Treatment of Parenteral Nutrition
Published by:
http://www.sagepublications.com
On behalf of:
The American Society for Parenteral & Enteral Nutrition
can be found at:Journal of Parenteral and Enteral
NutritionAdditional services and information for
http://pen.sagepub.com/cgi/alertsEmail Alerts:
http://pen.sagepub.com/subscriptionsSubscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
What is This?
- Jul 26, 2013OnlineFirst Version of Record >>
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from at SYRACUSE UNIV LIBRARY on
November 23, 2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/http://pen.sagepub.com/content/early/2013/07/26/0148607113496280http://pen.sagepub.com/content/early/2013/07/26/0148607113496280http://www.sagepublications.comhttp://www.sagepublications.comhttp://www.nutritioncare.orghttp://www.nutritioncare.orghttp://pen.sagepub.com/cgi/alertshttp://pen.sagepub.com/cgi/alertshttp://pen.sagepub.com/subscriptionshttp://pen.sagepub.com/subscriptionshttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsReprints.navhttp://www.sagepub.com/journalsPermissions.navhttp://www.sagepub.com/journalsPermissions.navhttp://pen.sagepub.com/content/early/2013/07/26/0148607113496280.full.pdfhttp://pen.sagepub.com/content/early/2013/07/26/0148607113496280.full.pdfhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://online.sagepub.com/site/sphelp/vorhelp.xhtmlhttp://pen.sagepub.com/http://pen.sagepub.com/http://pen.sagepub.com/http://pen.sagepub.com/
-
Journal of Parenteral and EnteralNutritionVolume XX Number X
Month 2013 1 16 2013 American Societyfor Parenteral and Enteral
NutritionDOI: 10.1177/0148607113496280jpen.sagepub.comhosted at
online.sagepub.com
Article
Background
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-testinal surgical procedures. Moreover, PN is especially
required in infants and children with intestinal failure (IF)
caused by a reduced absorptive surface (eg, short bowel syn-drome);
an intact, although inefficient, mucosal surface (eg, congenital
enterocyte disorders); or an intact mucosal surface with extensive
motility dysfunction (eg, chronic intestinal
pseudo-obstructions).1
However, patients on prolonged PN are at risk for a spec-trum of
PN-associated hepatobiliary disorders, ranging from cholestasis to
end-stage liver disease.2 Since its observation in early 1970s,3-5
PN-associated cholestasis (PNAC) has more often been found in
preterm neonates and infants, as it occurs earlier and hepatic
dysfunction can rapidly progress in these patients, therefore
remaining one of the most significant com-plications of prolonged
PN.8 Furthermore, infants and children
with IF are at risk for IF-associated liver disease (IFALD), the
most relevant and persistent complication in pediatric IF
496280 PENXXX10.1177/0148607113496280Journal of Parenteral and
Enteral NutritionLauriti et alresearch-article2013
From 1Department of Surgery, UCL Institute of Child Health,
London, UK; 2Department of Paediatric Surgery, G. dAnnunzio
University, Chieti-Pescara, Italy; and 3Division of General and
Thoracic Surgery, Hospital for Sick Children, Toronto, Canada.
Financial disclosures: The study was partly supported by grants
from the Mittal Research Foundation, London, UK. Agostino Pierro
and Simon Eaton have been consultants for the development of novel
parenteral amino acids mixtures and have consequently received
financial contributions from Fresenius-Kabi.
Received for publication April 23, 2013; accepted for
publication June 12, 2013.
Corresponding Author:Agostino Pierro, MD, FRCS(Eng), FRCS(Ed),
FAAP, Hospital for Sick Children, 555 University Ave, Suite
1526First Floor Hill Wing, Toronto, ON M5G 1X8, Canada. Email:
[email protected].
Incidence, Prevention, and Treatment of Parenteral
NutritionAssociated Cholestasis and Intestinal FailureAssociated
Liver Disease in Infants and Children: A Systematic Review
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
AbstractBackground: Cholestasis is a significant
life-threatening complication in children on parenteral nutrition
(PN). Strategies to prevent/treat PN-associated cholestasis (PNAC)
and intestinal failureassociated 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)
Keywordsparenteral nutrition; intestinal failure; cholestasis;
liver disease; child
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
2 Journal of Parenteral and Enteral Nutrition XX(X)
requiring long-term PN and the most consistent negative
prog-nostic indicator for their overall survival.1,7
Nonetheless, despite advances in the knowledge of bile
for-mation physiology8 and of the molecular basis for neonatal
cholestasis,9 both PNAC and IFALD are not completely eluci-dated
consequences of PN therapy in infants. A multifactorial etiology
has been proposed implicating low birth weight, pre-maturity,
enzyme deficiencies, genetic causes, anatomic fac-tors,
susceptibility to cholestatic injury, and factors relevant to the
PN itself.2,7,9-12 A further risk factor is the occurrence of
severe infections, due to the requirement for central line for
infusion of PN, and bacterial overgrowth caused by enteral
starvation and immature immune function.13
The prevalence of PNAC and IFALD varies considerably among
studies, but it is estimated to be approximately 40%-60% in infants
and up to 85% in neonates who are receiving long-term PN for IF.
Furthermore, the prevalence of the IFALD is unknown because there
is no established definition of liver disease in this setting and
it is unclear whether IFALD should be diagnosed on the basis of
clinical, biological, or histological criteria.1
Some children who receive long-term PN eventually develop
end-stage liver disease. Although their proportion was 15% in the
1990s,2 a more recent study suggests that careful 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 liver and/or intestinal
transplant.15,16 Furthermore, small bowel transplantation is
limited by a shortage of organ donors, espe-cially for premature
infants, and by 10 years, patient and intes-tine survival rate is
46% and 29% for intestine-only recipients, and 42% and 39% for
combined liver-intestine, respectively.17
Several enhancements in prolonged PN were achieved throughout
last decades, such as improvements in PN compo-nents and intensive
care measures. Aseptic placement tech-niques and strict catheter
care have reduced sepsis related to central line catheter.18
Moreover, no significant differences were noticed in the incidence
of catheter related-bloodstream infections in multiple lumen vs
single lumen catheters.19,20 However, there remains a risk of
septicaemia that could be due to bacterial translocation.21
In spite of these improvements, preventive strategies for both
PNAC and IFALD are limited and have reached moderate success, and
current therapies for these diseases have little sup-porting
evidence in infants.7,22 Even if the most effective treat-ment is
advancement to full enteral feeds and discontinuation of PN, this
process is often impossible because of poor intesti-nal function or
inadequate gut length.23 Therefore, PNAC and IFALD remain
significant life-threatening complications and 1 of the recognized
predictor factors of mortality in infants and children on long-term
PN.22
Currently, no systematic reviews are available on incidence of
both PNAC and IFALD in infants and children. An exhaus-tive review
summarizes current knowledge on PNAC, with
meticulous considerations in the prevention and treatment of
this disease.24 However, neither a systematic review on studies
included was done nor a precise definition of PNAC was men-tioned
by authors. A recent study systematically reviewed the potential
benefits and harms of -3 fatty acid lipid emulsions to prevent
complications associated with PN.25 However, the authors included
articles with nonhomogeneous characteristic, such as different
initial conditions of patients (eg, prematurity, patient with IF,
and infants with congenital heart disease), dif-ferent quality of
the studies (eg, randomized controlled trial, RCT, and cohort
studies with historical controls), and nonuni-form definition of
PNAC and IFALD. Furthermore, an article by Barclay et al26 reviewed
interventions in pediatric IF and its complications (sepsis and
IFALD). Although their systematic review did include measures taken
to prevent or treat cholesta-sis, authors did not mention any
definition of IFALD, conse-quently not all the studies included
were strictly related to this disease.
Hence, the aims of our systematic review were (1) to deter-mine
if the incidence of PNAC and IFALD have changed over time among
infants and children receiving PN for 14 days and if there is a
correlation between PNAC, IFALD, and length of PN; and (2) to
evaluate possible methods of prevention and treatment of PNAC and
IFALD.
Materials and Methods
Search Strategy
A systematic review of the Literature using defined search
cri-teria was performed (Figure 1). Studies published between 1950
and March 2013, using Medline, Embase, and the Cochrane Library
were searched. The following search terms were used: infant or
child or baby or paediatric or pediatric or neonate and parenteral
and liver or hepatic or hepatitis or cholestasis or bilirubin. The
explode function and the truncation terms $ and * were used as
appropriate to each database to search for all possible variations
of the keywords. This search strategy yielded 4696 articles. These
4696 titles and abstracts were screened indepen-dently by 2 authors
(GL and RA): Articles not relevant to PNAC or IFALD in infants and
children were excluded. Of all potentially relevant abstracts, 406
full-text articles were reviewed for the different inclusion
criteria. In addition, the same 2 authors screened the references
of all full-text articles to identify publications not retrieved by
the electronic searches. For individual selected studies 2 authors
(GL and AZ) indepen-dently graded the level of evidence (LoE)
presented using the Oxford Centre for Evidence-Based Medicine
Levels of Evidence methodology (Table 1).27
To obtain homogeneous collection of patients, included articles
were divided into 3 groups according to pediatric age or liver
disease both in incidence, prevention, and treatment analysis
(Table 2).
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 3
Incidence of PNAC and IFALD, their prevention, and their
treatment were analyzed (Figure 2). The inclusion criteria for
these parameters are reported below.
Incidence
In spite of different definitions of PNAC and IFALD and to gain
less biases, we determined to include in the present systematic
review only studies where cholestasis or liver disease were
defined as conjugated bilirubin (CB) 2 mg/dL (or 34 mol/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 to the risk of liver
failure.6,9-12,15,16,18 In addition, to avoid any synonymous use of
PNAC and IFALD, only articles with an explicit mention of IF were
included in the IFALD group.
Patients developing cholestasis for causes unrelated to PN (eg,
genetic or metabolic disorders, congenital infections, hae-molysis,
liver dysfunction, or extrahepatic obstructions) were excluded from
the study. Case reports and case series were excluded: Only
articles with 10 patients were considered in our systematic review.
Patients older than 18 years were not included.
Prevention
To gain stronger evidence for preventative, only prospective RCT
or cohort studies on prevention of PNAC and IFALD in infants and
children (age < 18 years) were included (LoE 1 and 2, Table 1).
Patients had to receive PN for 14 days, and not to have been
affected by cholestasis or liver disease (ie, CB had to be < 2
mg/dL) at the beginning of studies (Figure 2).
Treatment
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 IFALD were
defined as CB 2 mg/dL with PN 14 days (Figure 2).
Data Analysis
Incidence of cholestasis per decades (from 1970s to 2000s) and
per length of PN were assessed by chi-square test for trend.
Results showing P < .05 were considered significant. If
Figure 1. Search criteria applied to perform the systematic
review of the literature.
Table 1. The Oxford Centre for Evidence-Based Medicine Levels of
Evidence Methodology.27
LoE Prevention or Therapy Study Type
1a SR (with homogeneity) of RCTs1b Individual RCT (with narrow
confidence interval)1c All or nonea
2a SR (with homogeneity) of cohort studies2b Individual cohort
study (including low quality RCT)2c Outcomes research; ecological
studies3a SR (with homogeneity) of case-control studies3b
Individual case-control study4 Case-series (and poor quality cohort
and case-control
studies)5 Expert opinion without explicit critical appraisal, or
based
on physiology, bench research or first principles
LoE, level of evidence; RCT, randomized controlled trial; SR,
systematic review.aAll patients died before the medical
prescription became available, but some now survive on it; or when
some patients died before the medical prescription became
available, but none now die on it.
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 failureassociated liver disease; LBW, low birth weight;
PNAC, par-enteral nutritionassociated cholestasis; VLBW, very low
birth weight.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
4 Journal of Parenteral and Enteral Nutrition XX(X)
methodologically feasible, studies on prevention or treatment
were further compared by meta-analysis software (Review Manager,
RevMan version 5.2, Nordic Cochrane Centre, Cochrane Collaboration
2012, Copenhagen, Denmark).
Results
Incidence
Twenty-three articles (3280 patients) met the inclusion criteria
(Tables 3a and 3b).10,11,12,15,28-46 However, 1 study15 reported
only the median (with interquartile range, IQR) duration of PN.
The overall incidence of cholestasis coming from all included
studies was 29.9%, considering both PNAC and IFALD. Looking at
PNAC, the incidence of cholestasis was 28.2% and, respectively,
25.5% in preterm neonates (Group 1), and 30.6% in neonates at term
or not specified, infants, and children (Group 2; Table 3a). The
incidence of IFALD was 49.8% in pediatric patients with IF (Group
3; Table 3b).
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.
Five of the 14 articles included in Group 210,11,37-39 analyzed
the relationship between the duration of PN and PNAC (Table 4).
When possible, patients overlapping with Group 1 (ELBW and VLBW)
were excluded. The incidence of PNAC was
directly proportional to the length of PN, with an incidence
varying from 15.7% in patients receiving PN for 14-30 days up to
60.8% in patients receiving PN for >60 days (Figure 3; P <
.0001).
Furthermore, to examine the incidence of PNAC/IFALD throughout
the past 4 decades we considered only those
stud-ies10-12,15,30-32,34-40,44-46 with a precise study period
mentioned (Tables 3a and 3b, Figure 4a). Because of the paucity of
studies included in both Groups 1 and 3, it seemed no achievable to
determine any variation throughout past decades in these sub-groups
of patients. There appeared to be an alteration in the incidence of
PNAC over time in the Group 2,10,11,34-40 although it was not
possible to compare these data due to the overlap-ping periods that
the studies were conducted over (Figure 4b). Similarly, to reduce
bias resulting from including studies that were conducted over a
long period (with underlying improve-ment on PN during the study),
we examined the incidence of PNAC in only those studies with a
study period 5 years.10,11,34,36-38,40 Again, there was no obvious
alteration in the incidence of PNAC over time (Figure 4c).
Prevention
Ten studies met the inclusion criteria for prevention of the
dis-ease (Table 5).30,33,43,47-53 None of these articles were
related to IFALD. The articles included investigated possible
maneuvers to reduce the incidence of PNAC throughout choleretic
Figure 2. Inclusion criteria established to determine incidence,
prevention, and treatment of parenteral nutritionassociated
cholestasis. CB, conjugated bilirubin; PN, parenteral
nutrition.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 5
Table 3a. Studies on the Incidence of Parenteral
NutritionAssociated Cholestasis (PNAC) in Neonates, Infants, and
Children According to Study Period.
N Reference Study Period Age of Ptsa Indication for PN Days of
PN CB PNAC ptsPNAC
Incidence (%)
Group 1b
1 Slagle TA et al30 1985-1986 ELBW, VLBW
Prematurity 14 2 mg/dL 0/22 0
2 Baserga MC et al31 1998-2000 ELBW Prematurity 21 2 mg/dL
38/103 373 Costa S et al12 1996-2006 ELBW,
VLBWPrematurity 14 2 mg/dL 55/445 12.3
4 Christensen RD et al11
2002-2006 ELBW, VLBW, LBW
Prematurity 14 2 mg/dL 179/723 24.7
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 et al34
1972-1974 Neonates, infants
Surgery 14 2 mg/dL 8/19 42.1
7 Kubota A et al35 1971-1982 Neonates n.m. 14 2 mg/dL 44/77 578
Vileisis RA et al36 1977-1978 Neonates Prematurity,
surgery, RDS14 2 mg/dL 11/33 33.3
9 Kubota A et al35 1983-1987 Neonates n.m. 14 2 mg/dL 22/72 3110
Beath SV et al37 1988-1992 Neonates Surgery 28 >2.35 mg/dL 27/74
36.511 Forchielli ML
et al381990 Infants Prematurity,
surgery, sepsis, ECMO
14 2 mg/dL 15/70 21.4
12 Kubota A et al35 1992-1996 Neonates n.m. 14 2 mg/dL 31/124
2513 Wright K et al10 1997-1999 Neonates n.m. 21 2 mg/dL 24/141
1714 Jensen AR et al39 1996-2007 Neonates Gastroschisis 21 2 mg/dL
16/71 22.515 Christensen RD
et al112002-2006 LBW,
neonatesPrematurity,
surgery, ECMO14 2 mg/dL 178/643 27.7
16 Nehra D et al40 2007-2011 Neonates Surgical gastrointestinal
condition
21 2 mg/dL 14/32 43.8
- Farrell MK et al41 n.m. Infants, children
n.m. >15 2 mg/dL 6/55 10.9
- Puntis JWL et al42 n.m. Neonates Prematurity, NEC, PDA,
surgery, abdominal distension
>14 >2.35 mg/dL 9/53 17
- Drongowski RA et al29
n.m. Neonates n.m. >49 2 mg/dL 17/32 53.1
- Teitelbaum DH et al28
n.m. Neonates n.m. >14 2 mg/dL 9/21 43
- Fok TF et al43 n.m. Neonates Prematurity, feed intolerance,
sepsis, NEC, surgery, others
>14 >2.94 mg/dL 58/78 74.4
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
nutritionassociated cholestasis; RDS, respiratory distress
syndrome; VLBW, very low birth weight.aAge of patients at the
beginning of PN.bGroup refers to Table 2.
agents,47,48 antibiotic therapy,49-51 and improvement in
nutrition intake, enhancing components of PN, such as protein,
trace elements, or lipids,43,53 and supporting enteral
nutrition30,33 or PN cycling.52
Choleretic agents. Trying to improve intrahepatic and
extrahepatic bile flow and biliary sludge, Teitelbaum et al47
evaluated the effects of cholecystokinin (CCK, 0.04 g/kg per dose,
i.v., every 12 hours for 14 days) on the development of
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
6 Journal of Parenteral and Enteral Nutrition XX(X)
severe PNACdefined as CB levels of 5.0 mg/dLin a neonatal
population. CCK failed to prevent severe PNAC (Table 5). The study
was a RCT recruiting initially only severely premature infants
(< 1000 g at birth and with an esti-mated gestational age of
< 28 weeks, Group 1) and afterward also surgical neonates (<
30 days of age at the time of enrol-ment, Group 2). Therefore, we
assigned to this study a LoE 2b.
The prospective study by Heubi et al48 investigated the
prophylactic effect of tauroursodeoxycholic acid (TUDCA, 30
mg/kg/day) in the development of PNAC. As shown in Table 5, TUDCA
failed to show any effect in preventing PNAC. Because of
difficulties in enrolment, authors proceed
with an open-label trial with comparison of concurrently
untreated controls who refused participation. The population
included in the study was heterogeneous, including ELBW and VLBW on
one hand (Group 1), but also neonates with a birth weight > 1500
g (Group 2). Furthermore, some of the infants treated with TUDCA
had been submitted to wide intestinal resection. Therefore, results
regarding the effects of TUDCA should be interpreted with caution
in infants with short bowel syndrome, since the length of remnant
ileum is essential to ensure bile acid absorption and thus,
possible effect of TUDCA in such condition. For these reasons, the
article was rated at LoE 2b.
Table 3b. Studies on the Incidence of Intestinal
FailureAssociated Liver Disease (IFALD) in Pediatric Population
(Group 3, see Table 2) According to Study Period.
N Reference Study Period Age of Ptsa Indication for PN Days of
PN CBIFALD
PtsIFALD
Incidence (%)
Group 3: Neonates, infants, and children with IF
17 Quirs-Tejeira RE et al44
1975-2000 Infants, children SBS >90 2 mg/dL 18/78 23
18 Sondheimer JM et al45
1984-1997 Infants Surgery 90 2 mg/dL 28/42 67
19 Wales PW et al15 1997-2001 Neonates SBS Median 86ddb >2.94
mg/dL 25/40 62.520 Kglmeier J et al46 2001-2002 Infants, children
Prematurity,
surgery, oncology>28 2.94 mg/dL 55/93 59.1
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.aAge of patients at the beginning of
PN.bPNAC reported after a median of 86 days of PN (interquartile
range, IQR, 55-138 days).
Table 4. Relation Between the Incidence of Parenteral
NutritionAssociated 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
0Forchielli ML et al38 15-21 0/19 0Christensen RD et al11 14-28
55/365 15Wright K et al10 14-30 5/123 4.1Forchielli ML et al38
22-28 2/6 33.3Jensen AR et al39 25 16/71 22.5Beath SV et al37 28
27/74 36.5 Duration of PN 30-60 days Forchielli ML et al38 29-42
2/8 25Christensen RD et al11 29-56 38/77 46Wright K et al10 31-60
10/68 14.7Forchielli ML et al38 43-56 0/5 0Jensen AR et al39 50
35/71 49 Duration of PN > 60 days Wright K et al10 61-90 5/14
35.7Christensen RD et al11 57-100 12/17 71Forchielli ML et al38
>56 9/14 64.3Wright K et al10 91-120 3/4 75Christensen RD et
al11 >100 1/1 100Wright K et al10 121-150 1/1 100
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 7
Figure 3. Incidence of parenteral nutritionassociated
cholestasis (PNAC) was directly proportional to the length of
parenteral nutrition (PN) in Group 2, assessed by chi-square test
for trend: P < .0001. Data are expressed as means.
Antibiotic therapy. With regard to antibiotic treatment, 2
dif-ferent RCTs49,50 focused on the possible prevention of PNAC
with erythromycin in VLBW neonates (Group 1). In the first one,49
high-dose of oral erythromycin (12.5 mg/kg/dose every 6 hours for
14 days) significantly lowered the incidence of PNAC in treated
neonates (18/91, 20%) in comparison with controls (37/91, 41%; P =
.003, Table 5). Moreover treated infants achieved full enteral
nutrition significantly earlier (P < .001), the duration of PN
was significantly decreased by 10 days (P < .001), and fewer
infants receiving erythromycin had 2 or more episodes of
septicaemia compared with placebo patients (P = .03). The RCT was
well-constructed, with possi-ble low confounding bias given by his
duration. It was con-ducted in 2 phases, during 2 periods,
resulting in an overall length of approximately 8 years. Even if
all VLBW infants were routinely started on the same PN, we could
not assume the nonexistence of any further benefit coming from any
sort of up-to-date protocols or therapies in such long time.
However, the article was rated at LoE 1b. In the second RCT50
intermedi-ate-dose of oral erythromycin (5 mg/kg/dose every 6 hours
for 14 days) significantly lowered the incidence of PNAC in treated
neonates (2/19, 10.5%) in comparison with controls (10/26, 38.5%; P
< .05, Table 5). Moreover, the number of days required to
achieve full enteral feeding (P = .01), the duration of PN (P <
.05), and the time required to achieve a body weight 2500 g (P <
.05) were significantly shorter in treated infants. Furthermore,
the incidence of necrotizing enterocolitis (NEC) stage IIa after 14
days of treatment was significantly lower in the erythromycin group
(P < .05). The RCT was well-constructed, with adequate power
calculation of the sample size, and without significant confounding
bias within cases and controls, even if the authors did not
mention
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 with added
premature infant formula, whereas controls received standard PN
with amino acids and enteral premature 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, as the authors did not mention any methods of
randomization or describe the use of power calculations that lead
to the num-bers recruited and did not state about concurrent
administration of further treatments. Moreover, the number of
patients recruited was too undersized. These possible risks of
con-founding biases lead this study to be assigned a LoE 2b.
Similarly, Slagle et al30 evaluated the potential benefit of
early low-volume feedings in very low birth weight (VLBW) neonates
in an RCT (Table 5). Although neither early-feeding infants nor
delayed feeding patients developed PNAC, the mean serum
concentrations of CB for VLBW in the early feed-ing group were
slightly lower than those in the delayed feeding group on day 18
(0.2 0.02 mg/dl vs 0.3 0.05 mg/dl) and day 29 of life (0.2 0.02
mg/dl vs 0.3 0.05 mg/dl, P < .05; data expressed mean SEM).
Leaving aside the lack of methodol-ogy used for the power
calculation, the modest number of patients recruited, and the epoch
of the study, what it might be surprising is that delayed feeding
group did not demonstrate any rising in CB after 15 days of total
PN (0.3 0.03 mg/dl vs 0.3 0.05 mg/dl). Moreover, PN was initiated
in all patients on day 3 of life and was increased uniformly over 4
days (until randomization to total PN or early oral feeding), so
that we do not have any data about alimentation on day 1 and 2 of
life, as well as further concurrent feeding from day 3 to day 7.
The article was then rated at LoE 2b.
Salvador et al52 compared the incidence of PNAC in VLBW infants
receiving cycle PN (amino acid solution, TrophAmine, B. Braun
Medical, Irvine, CA, over a 20-hour period, a soy-bean-based lipid
emulsion, Intralipid 20%, Fresenius Kabi, Homburg, Germany, over 18
hours, and dextrose over 24 hours) and those receiving continuous
PN (TrophAmine over a 24-hour period, Intralipid 20% over 18 hours,
and dextrose
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
8 Journal of Parenteral and Enteral Nutrition XX(X)
over 24 hours). However, the incidence of PNAC was similar in
the 2 groups (32% and 31%, respectively; P = ns; Table 5). The RCT
was well-constructed, with adequate methods of ran-domization,
without significant confounding bias within cases and controls,
even if no power calculation of the sample size has been mentioned.
The study was then rated at LoE 1b.
To enhance components of PN, Vileisis et al53 compared in a RCT
the hepatic effects of 2 different parenteral protein intakes, a
lower protein regimen (LP: 2.3 g/kg/day) and a higher protein
regimen (HP: 3.6 g/kg/day) in patients with structural
gastroin-testinal defect, NEC, and extreme prematurity with RDS
(Groups 1 and 2; Table 5). Although the incidence of PNAC in the LP
and HP groups were very similar (27% and 33%, respec-tively; P =
ns), infants randomized to the HP group developed PNAC earlier than
the LP group (27 4 vs 47 6 days; P < .01), and achieved a
significantly greater peak of CB (8.4 1.6 vs 3.2 0.3 mg/dl; P <
.001; data expressed mean SEM). Leaving out the time of the study,
the inclusion criteria to recruit patients were indefinite, as
authors did not mention further information on the structural
gastrointestinal defect, such as on
subsequent surgical procedures, thus omitting potential wide
intestinal resection. Furthermore, even if authors included extreme
prematurity neonates with RDS, birth weights were 2.4 0.2 kg in LP
and 2.7 0.2 kg in HP, with gestational ages of 36.0 0.8 and 37.7
0.9 weeks, respectively, thus likely reduc-ing the numbers of ELBW
and VLBW neonates recruited. The article was rated at LoE 2b.
Fok et al43 randomized preterm and at term neonates (Group 2) to
receive either 1 or 0.0182 mmol/kg/d of manganese sup-plementation
in a high-quality RCT (Table 5). Although there was no significant
difference in the occurrence of PNAC (58/78 vs 49/82; P = .073),
significantly more infants in the high man-ganese group developed
severe conjugated hyper-bilirubinaemia, with peak serum CB > 100
mmol/L (5.9 mg/dL) in 32/78 patients vs 20/82; P = .038. The RCT
illustrated well-constructed methods, even if there were some low
risk biases in the high manganese group, such as slightly smaller
gestational age (31.0 3.9 vs 32.0 4.8, respectively; mean SD),
higher number of neonates with NEC (42.3 vs 34.1%), lower days of
age when PN started (5.0 {4.0, 7.0} vs 5.0 {4.0, 8.0}), and more
days on PN
Figure 4. (a) Included studies on incidence of parenteral
nutritionassociated cholestasis (PNAC) or intestinal
failureassociated 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.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 9
Figure 5. Meta-analysis on 2 different doses of erythromycin to
prevent parenteral nutritionassociated cholestasis (PNAC). Ery,
erythromycin; QDS, quater die sumendus, 4 times a day.
Table 5. Studies on Prevention of Parenteral NutritionAssociated
Cholestasis (PNAC) in Children.
Reference Groupa Treatment Study Design (ratingb)PNAC in Treated
Pts (incidence %)
PNAC in Untreated Pts (incidence %) P Value
Choleretic agentsTeitelbaum DH et al47 1,2 Cholecystokinin
(0.04
g/kg/12 hours)RCT (2b) 10/114 (9) 13/111 (12) ns
Heubi JE et al48 1,2 Tauroursodeoxycholic acid (30
mg/kg/day)
Prospective nonrandomized (2b)
22/22 (100) 32/32 (100) ns
AntibioticsNg PC et al49 1 Erythromycin (12.5
mg/ kg/6 hours)
RCT (1b) 18/91 (20) 37/91 (41) .003
Ng YY et al50 1 Erythromycin (5 mg/kg/6 hours)
RCT (1b) 2/19 (10.5) 10/26 (38.5)
-
10 Journal of Parenteral and Enteral Nutrition XX(X)
most serious complication in patients with IF receiving
long-term PN, and it is the most consistent negative prognostic
indi-cator for overall survival in these patients.7
Nonetheless, many weak points are still present in the
lit-erature on both PNAC and IFALD. With regard to the defini-tion
of cholestasis and liver disease, they are conventionally defined
as CB 2 mg/dL (or 34 mol/L) in pediatric popula-tion. Although the
cutoff value is considered arbitrary and does not necessarily
correlate with any specific hepatic pathology, it has been
extensively used in pediatric studies.28,46 Furthermore, the
definition of PNAC and IFALD are not standardized, even if one of
the most commonly definition used is CB 2 mg/dL (or 34 mol/L) in
association with a duration of PN 14 days.2,28,29,47 These brought
to heterogeneity between different studies in this field. Moreover,
to the knowledge of authors, no systematic review has been
published on incidence, preven-tion, and treatment of PNAC and
IFALD. As mentioned, an up-to-date systematic review on -3 fatty
acid lipid emul-sions25 included nonhomogeneous articles on both
PNAC and IFALD without a definite definition of PNAC and IFALD.
Moreover, a systematic review on pediatric IF26 did not men-tion
any definition of IFALD. We acknowledge that our a priori
definitions (eg, CB, length of time on PN) as inclusion criteria
for the systematic review may have excluded some relevant articles,
but this was necessary to decrease bias and potential subjective
inclusion or exclusion of articles.
Incidence
Despite improvements in surgical procedures, intensive care unit
(ICU) management, involvement of nutrition support teams, as well
as in the composition and mode of delivery of PN, both the
incidence of PNAC and IFALD remain high with special concern in
young infants.56 In the present systematic review, only articles
with a homogenous definition of cholesta-sis related to PN and IF
were included (Figure 2).
The overall incidence of PNAC and IFALD in the studies included
ranged from 0% to 74.4% (mean 29.9%). Because the incidence of PNAC
could be age-related, with a higher inci-dence in
very-low-birth-weight infants, we separated studies on ELBW and
VLBW (Group 1) from remaining (Group 2). A further group (Group 3)
was assessed to articles exclusively focused on IFALD. We did not
notice any obvious relationship between age of patient and
incidence of PNAC, although only a few articles included children
(Table 3a). In contrast with what we expected, preterm neonates in
Group 1 demonstrated a lower incidence of PNAC vs neonates,
infants, and children in Group 2 (25.5 vs 30.6%, respectively).
This result could be biased by not specified preterm neonates
included in studies of Group 2 (eg, Fok et al43 studied neonates
with a mean birth weight of 1347 g).
A further bias, given by different length of PN, was eluci-dated
in the Group 2 (Figure 3): as expected the development of PNAC is
closely related to the duration of PN. This
association was first noted by Beale et al58 who showed that the
incidence of cholestasis (defined as CB 1.5 mg/dL) was 10% after 10
days of PN but increased to 90% in those treated for >3 months.
This correlation could also explain the higher inci-dence of IFALD
in pediatric IF, because of the longer PN (ie, PN > 28 days,
Table 3b). However, because of the paucity of studies included in
Group 3, no further significant subanalysis were feasible on the
incidence of IFALD in patients with long-term PN.
There has been no obvious decrease in the incidence of both PNAC
and IFALD over the last 40 years. Because of the lack of studies
exclusively on preterm neonates (Group 1) and on IFALD (Group 3),
we could not achieve any consideration on these patients (Figure
4a). With regard to the Group 2, patients are heterogeneous in the
populations of infants described, both in terms of patient age and
indication for PN (ie, surgical vs medical). Furthermore, since
most of the study periods are overlapping, no strict decreasing
incidence of PNAC was reached in this group (Figures 4b and 4c). In
addition, it must be noted that there appeared to be a lack of
recent data in inci-dence of both PNAC and IFALD during the second
half of past decade. Because of this, none of the articles that met
our inclu-sion criteria used the novel lipids that have seen
widespread introduction over the past 5 years. It remains to be
established whether the use of such lipids could decrease the
incidence of PNAC.
Prevention
Even though there have been numerous studies aimed at
pre-venting PNAC or IFALD, many of these were excluded as they were
retrospective case series. There were only a few articles in which
interventions were prospectively evaluated. Moreover, only some of
them met our inclusion criteria to define PNAC. As a result, no
prospective studies on IFALD were included, because of different
(or lack) definition of the disease. There is evidence of
beneficial effect of the management by multidisci-plinary teams
with pediatric gastroenterology, pediatric sur-gery, transplant,
and immunology.59 Advances such as the introduction of
multidisciplinary teams and protocolization, in addition to
specific therapeutic or surgical modulations, have improved the
outlook for both PNAC and IFALD has changed considerably in the
last decade; fewer children undergo intesti-nal transplantation and
waitlist mortality for children listed for intestine
transplantation has also decreased.17,60,61
Choleretic agents. None of the 2 included studies on cho-leretic
agents to prevent PNAC in Groups 1 and 2 of patients showed a
significant benefit to either TUDCA or CCK (Table 5).47,48 A
previous study with lower doses of CCK (0.02 g/kg per dose, i.v.,
every 12 hours for 14 days) failed to prevent development of PNAC
in severe preterm neonates.28 This arti-cle was excluded because
authors compare prospective cases with a historical cohort of
controls (LoE 4).
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 11
Further RCTs on PNAC in Group 262 and Group 163 of pre-term
neonates demonstrated that ursodeoxycholic acid (UDCA)
significantly decreased serum -glutamyl transferase activity (a
widely and early sensitive used marker in detecting PNAC) during
PN, associated with an earlier, albeit not signifi-cant,
achievement of full enteral feeding. Both trials were excluded from
the systematic review as no definition of cho-lestasis was
included. Even if the first study62 was a high-quality RCTs (LoE
1b), the latter63 compared cases to control neonates with
significantly lower gestational age and birth weight (LoE 2b).
However, due to these encouraging results, the role of UDCA in
preventing PNAC may warrant further investigation.
Antibiotic therapy. Intraluminal bacterial overgrowth with
subsequent translocation and sepsis, catheter related sepsis, and
any other conditions that produce a systemic inflammatory response,
such as NEC, are closely associated with PNAC.64 Despite this,
studies with 2 doses of MNZ prophylaxis in Group 2 of patients
failed to show any benefit (Table 5).51
In contrast, both high and intermediate-dose of oral
erythro-mycin (12.5 mg/kg/dose, and 5 mg/kg/dose every 6 hours for
14 days, respectively)49,50 were shown to decrease the inci-dence
of PNAC and septicaemia in 2 RCTs on Group 1 of pre-term neonates
(Table 5). The meta-analysis on these 2 RCTs (Figure 5)
corroborates the beneficial effect of erythromycin in preventing
PNAC (P < .001). However, this effect may be mediated via the
prokinetic effects of erythromycin rather than its antibiotic
effects. Moreover, these results are homogeneous to the significant
evidence that high-doses of erythromycin, even when administered
orally, can reduce the time required by premature infants with
nonobstructive gastrointestinal dys-motility to achieve full
enteral nutrition, and thus reduce their dependence on PN.
Furthermore, none of the RCTs published so far reported any major
side effects, in particular, hypertro-phic infantile pyloric
stenosis and life-threatening cardiac dys-rhythmia.65 However, even
if oral erythromycin was demonstrated to reduce the incidence of
PNAC in VLBW, results obtained in this particular subset of
patients could not be extrapolated in neonates at term or in older
group of patients with IF (Groups 2 and 3). Furthermore, uncommon
untoward effects, long-term effects on the bowel microflora and the
pos-sibility of promoting emergence of multidrug-resistant
organ-isms in the neonatal ICU, have not been fully evaluated,66 so
that oral erythromycin should be used cautiously and selec-tively
in preterm infants at higher risk for PNAC.
Nutritional intake. A way to prevent PNAC is to reach full
enteral feeding and cease PN supplementation. Two RCTs included in
our systematic review on Group 1 preterm neo-nates (Table 5)
investigated the use of early enteral feeds to prevent PNAC in
severe preterm neonates.30,33 Both RCTs did not reach high LoE2band
only the study on aminoacid-free PN with enteral bovine whey
protein demonstrated
significant prevention of PNAC in comparison with controls.33
Even if the study was focused on severe preterm neonates (Group 1),
we believe that amino acid-free PN would not be acceptable for any
other than very individualized use, thus restricting its employment
in those who tolerate early enteral feeds with premature infants
formula added with whey protein.
Furthermore, some,67,68 but not all,69,70 studies excluded from
this systematic review support early enteral feeding. All studies
but 168 were exclusively on Group 1 neonates and did not meet the
inclusion criteria because of short-term PN67,68,70 or lack of
definition of PNAC.69 Moreover, the dated RCT by Dunn et al67
demonstrated high risk of biases given by vague inclusion and
exclusion criteria and the small number of neo-nates involved (LoE
2b), and the RCT by Leaf at al68 included a slightly higher
proportion of infants 1250 g in the early group. In addition, all
these prevention studies were performed predominantly or
exclusively on severe preterm neonates (Group 1),30,33,67,70 and
some procedures (ie, early low volume feeding or aminoacid-free PN
with enteral whey proteins) are not applicable in older children or
in pediatric IF (Groups 2 and 3). Subsequently, further prospective
studies are needed to cor-roborate the benefit of these procedures
both in severe preterm neonates and in older pediatric
patients.
Although 2 retrospective articles39,71 on Group 2 of neo-nates
(LoE 4) demonstrated that cyclic PN may be associated with a
decreased incidence or, perhaps, delay in onset of PNAC, the RCT
included on this manoeuvre52 did not reach any beneficial effect in
cycling PN to prevent PNAC in VLBW. This result could be expected
as the only difference between the 2 groups was the length of
administration of the amino acid solution (over 20 hours in the
group with cycle PN vs over 24 hours in those with continuous PN),
with presumably the same final daily amount of the solution in the
2 groups. Moreover, the length of administration of the
soybean-based lipid emul-sion in both groups was equal (over 18
hours).
As well as specific interventions undertaken to prevent PNAC or
IFALD, there may be other ways to reduce its inci-dence. Sigalet et
al72 showed in Group 3 of patients the impor-tance of a
multidisciplinary team and a protocol-driven strategy to prevent
IFALD. No episode of severe cholestasis (CB > 100 mol/L for >
2 months) occurred in the cohort of patients fol-lowed by the
multidisciplinary team in comparison with an incidence of 28% in an
historical cohort of controls. However, because of the presence of
the historical cohort of controls, this study did not meet our
inclusion criteria (LoE 4).
Even if several improvements in components of PN have been
achieved throughout last decades, only 2 included articles
evaluated enhancements in elements of PN.43,53
In Groups 1 and 2 of patients, Vileisis et al53 demonstrated
that a LP regimen could be beneficial in reducing incidence of
PNAC. However, a LP regimen could have an adverse impact on growth.
Furthermore, the group of infants who presented with cholestatic
jaundice were exposed to a significantly longer
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
12 Journal of Parenteral and Enteral Nutrition XX(X)
PN and received also a significantly higher glucose supply as
compared with infants without cholestatic jaundice, thus achieving
a LoE 2b. Therefore, the role of aminoacid intake was hardly
assessed.
In a good-quality RCT (LoE 1b) on Group 1 neonates, Fok et al43
showed that manganese supplementation in excess of recommendations
causes a more severe degree of conjugated hyperbilirubinaemia.
However, most centers use a trace ele-ment solution that provides
manganese at recommended lev-els. It is not known whether a further
decrease in manganese intake could affect cholestasis.
In the same field, Spencer et al73 observed in post hoc data
analysis of a prospective study on Group 2 of infants (LoE 3b) that
taurine supplementation did offer a very significant degree of
protection against PNAC compared with no taurine. However, as
infant PN amino acid solutions now contain tau-rine, whether there
could be any benefit of increased taurine supplementation is
unknown.
Even if glutamine supplementation during PN did not reduce the
incidence of sepsis in Group 2 of infants with surgi-cal
gastrointestinal disease,74,75 it is still debated whether its role
in the maintenance and repair of gastrointestinal mucosa may
prevent PNAC/IFALD by protecting the hepatic function. A pilot
RCT75 with inadequate sample size (LoE 2b) on Group 2 of infants
with surgical gastrointestinal disease showed that enteral
glutamine supplementation had no apparent effect on the duration of
PN, tolerance of enteral feeds, or intestinal absorptive or barrier
function. However, a more recent RCT76 with insufficient sample
size (LoE 2b) on Group 1 of infants demonstrated that parenteral
glutamine supplementation pres-ents a protective effect on the
liver by decreasing the serum levels of aspartate aminotransferase
and total bilirubin (P < .05), even if no significant difference
was noticed with regard to direct bilirubin. High-quality RCT would
be required to bet-ter assess the benefit of this maneuver.
There were a few articles evaluating the possible beneficial
effect of other elements of PN which were excluded because they
were retrospective, in patients on short-term PN, or because of the
lack of a clear definition of PNAC. Among these, a
medium-chain:long-chain triacylglycerol 50:50 mix-ture demonstrated
some potential benefits in an adequate-quality RCT (LoE 2b) on
Group 2 of patients, excluded because of the lack of definition of
PNAC.77 This mixture could warrant fur-ther investigation.
A novel lipid emulsion containing a mixture of soybean oil,
medium-chain triglycerides, olive oil, and fish oil (SMOFlipid,
Fresenius Kabi, Bad Homburg v.d.h., Germany) showed some benefits
in a well-constructed RCT (LoE 1b) on Group 2 patients on
short-term PN (7-14 days).78 Two RCTs of SMOFlipid vs Intralipid
for prevention of PNAC in Group 1 of infants79 and in Group 2 of
infants with IF/SBS80 are currently ongoing.
Although early reports of success and safety with the use of
Omegaven in reversal of PNAC23,54-56 might suggest that it
may be useful in the prevention on PNAC, in a retrospective
analysis of prospectively collected data on Group 2 of neonates
Nasr et al81 have stated that with >80% of PNAC patients being
weaned from PN without adverse hepatic sequelae, it is diffi-cult,
in the absence of definitive evidence of efficacy and safety for
Omegaven together with increased costs, to justify its routine use
in a low-risk population (such as the surgical neonates with mild
parenteral nutritionassociated liver dys-function examined in the
study) outside formal research proto-cols. To this end, there are
various RCTs on the use of new lipid emulsions to prevent/treat
PNAC or IFALD currently regis-tered for recruitment. One RCT of
Omegaven vs Intralipid in preventing PNAC in Group 2 of infants
with IF is currently completed albeit not published.82
Treatment
Currently there is no truly effective pharmacologic manage-ment
of both PNAC and IFALD. Maneuvers to treat these dis-eases are
limited (bile acid-binding agents, choleretics such as ursodiol,
cycling of PN administration, and limitation of trace minerals in
PN) and have little supporting evidence in infants. One RCT of UDCA
vs placebo for treating PNAC in Group 2 of neonates is currently
recruiting participants.83
A prospective study from Cober et al84 demonstrated that an
intravenous (IV) fat emulsion reduction in PN to 1 g/kg/d 2 times
per week in neonates diagnosed with PNAC significantly decline the
total bilirubin levels compared with controls (P < .01) and
significantly shortened the days on PN (P < .05). However,
because of the presence of the historical cohort of controls, this
study did not meet our inclusion criteria and reached a low LoE
(LoE 4).
The novel lipids described above have also been evaluated for
their ability to reverse PNAC/IFALD. There is increasing enthusiasm
because of the early reports of success and safety with the use of
Omegaven to reverse PNAC/IFALD in infants and children.54-56,85-92
However, most of these studies were ret-rospective,85-87,92
prospective with no controls,88-90 or prospec-tive with historical
cohort of controls,54-56 so that there are no current data from
high-quality prospective RCTs.89,92 Three studies from the same
authors54-56 compared prospective groups treated with the
fish-oil-based fat emulsion vs historical cohorts of infants (Group
2) treated with Intralipid (LoE 4). Patients receiving Omegaven had
a significantly higher rever-sal of cholestasis while on PN (P <
.0001), also in the study where the fat doses were identical in
both groups.55 One RCT of Omegaven vs Intralipid minimization for
treating severe PNAC in Group 2 of patients is currently
ongoing.93
Furthermore, SMOFlipid, in an excluded good-quality RCT (LoE
1b), significantly reduced total bilirubin levels compared with
Intralipid in infants and children (Group 2) receiving home PN.94
Therefore, despite the promise that alternate lipid strategies may
have, at present the use of these novel lipids remains
investigational and should be restricted to those with
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 13
severe PNAC/IFALD unless in the context of a RCT examin-ing
their safety and efficacy as a preventative strategy.89
Among choleretics, UDCA was tested in a few stud-ies,95-99
although only 2 study designs were prospective,95,96 and only 1 of
them was a case-control study, albeit retrospec-tive97 (all studies
at LoE 4). Thus none of these articles met our inclusion criteria,
even if UDCA may warrant further investi-gation as there appeared
to be a reversal of cholestasis in all but 1 study.98 Two
preliminary reports with no controls evaluated the role of CCK in
Group 2 of infants with PNAC.100,101 Both of them showed that CCK
appears to be associated with a decline in CB levels, so that
cholestasis may be reversed by IV CCK in the majority of patients.
Other studies not included in our review (inclusion criteria not
met) assessed the beneficial effects of enteral nutrition together
with ursodiol in Group 2 of infants102 or with more composite
intestinal rehabilitation pro-gram in Group 3 of patients.103,104
Even if none of these articles were prospective neither
case-control designed (LoE 4), all achieved a reduction or reversal
of cholestasis, which may indicate the importance of an aggressive
weaning of PN to enteral nutrition in infants with both PNAC or
IFALD.
Ultimately, irrigation of the biliary tract may provide
bene-fits by flushing out unexcreted remnants; a retrospective
case-control study (LoE 4) by Wales et al105 suggested that
percutaneous transhepatic transcholecystic cholangiography may be
effective in Group 2 of surgical neonates with PNAC.
Conclusions
The incidence of PNAC is directly correlated to the length of
PN. This correlation is corroborated by the higher incidence of
IFALD in pediatric IF, because of the longer PN. Despite
improvements in the management of infants and children requiring PN
and the control of infections, the incidence of both PNAC and IFALD
in children does not appear to have decreased over the past 4
decades.
There is a lack of high quality prospective study to
prevent/treat these diseases, especially on IFALD. The only
interven-tions which have been shown to significantly prevent
develop-ment of PNAC are limited to severe preterm neonates. They
demonstrated benefits in preventing PNAC given by both high and
intermediate-dose of oral erythromycin49,50 or by an
ami-noacid-free PN associated with enteral feeding with premature
infant formula and whey protein.33 However, both maneuvers might
warrant additional examinations and further prospective studies are
mandatory to corroborate these results.
Omegaven and SMOFlipid may have benefits in prevention and/or
reversal of PNAC and IFALD, although the evidence for their use is
currently limited. Consequently, there is a requirement for further
RCTs to better assess prevention and treatment maneuvers against
both PNAC and IFALD in infants and children. However, we
acknowledge that sometimes per-forming RCTs is simply impossible,
and then we are left with lower levels of evidence. For example,
the introduction of
multidisciplinary teams to treat patients with or at risk of
PNAC/IFALD has almost certainly improved the outcomes and it would
be unethical and impossible to design a study ran-domizing patients
to receive or not receive care from such a team. Similarly, in
Europe at least, where novel lipids were initially licensed and
already very widely used, it is extremely difficult to design an
RCT of treatment of established PNAC/IFALD where 1 arm would
exclusively receive soy-based lip-ids. In scenarios such as these
prospective or retrospective studies, despite offering lower levels
of evidence, may be the best we can hope for. One other possibility
for these rare disor-ders is to expand the role of registries. A
registry exists for the STEP procedure, for example, but its
effectiveness is limited by the lack of comparative data (eg,
alternative surgical proce-dures, medical therapy, etc).
References
1. Kelly DA. Liver complications of pediatric parenteral
nutrition: epidemi-ology. Nutrition. 1998;14:153-157.
2. Touloukian RJ, Downing SE. Cholestasis associated with
long-term par-enteral hyperalimentation. Arch Surg.
1973;106:58-62.
3. Peden VH, Witzleben CL, Skelton MA. Total parenteral
nutrition. J Pediatr. 1971;78:180-181.
4. Rager R, Finegold MJ. Cholestasis in immature newborn
infants: is paren-teral alimentation responsible? J Pediatr.
1975;86:264-269.
5. De Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral
fish oil monotherapy in the management of patients with parenteral
nutrition-associated liver disease. Arch Surg.
2010;145:547-551.
6. DAntiga L, Goulet O. Intestinal failure in children: the
European view. J Pediatr Gastroenterol Nutr.
2013;56(2):118-126.
7. Soden JS. Clinical assessment of the child with intestinal
failure. Semin Pediatr Surg. 2010;19:10-19.
8. Emerick KM, Whitington PF. Molecular basis of neonatal
cholestasis. Pediatr Clin North Am. 2002;49:221-235.
9. Carter BA, Shulman RJ. Mechanisms of disease: update on the
molecular etiology and fundamentals of parenteral nutrition
associated cholestasis. Nat Clin Pract Gastroenterol Hepatol.
2007;4:277-287.
10. Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM.
Increased incidence of parenteral nutrition-associated cholestasis
with aminosyn PF compared to trophamine. J Perinatol.
2003;23:444-450.
11. Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert
DK. Identifying patients, on the first day of life, at high-risk of
developing par-enteral nutrition-associated liver disease. J
Perinatol. 2007;27:284-290.
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-teral nutritionassociated cholestasis. J
Pediatr. 2010;156:575-579.
13. Koletzko B, Goulet O. Fish oil containing lipid emulsion in
parenteral nutrition-associated cholestatic liver disease. Curr
Opin Clin Nutr Metab Care. 2010;13:321-326.
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-ence in 302 patients. J Pediatr Gastroenterol
Nutr. 2007;44:347-353.
15. Wales PW, de Silva N, Kim JH, Lecce L, Sandhu A, Moore AM.
Neonatal short bowel syndrome: a cohort study. J Pediatr Surg.
2005;40: 755-762.
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 syndrome using intravenous fish
oil in combination with omega-6/9 lipid emulsions. J Pediatr Surg.
2011;46:1361-1367.
17. Mazariegos GV, Steffick DE, Horslen S, et al. Intestine
transplantation in the United States, 1999-2008. Am J Transplant.
2010;10:1020-1034.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
14 Journal of Parenteral and Enteral Nutrition XX(X)
18. Kelly DA. Intestinal failureassociated liver disease: what
do we know today? Gastroenterology. 2006;130:S70-77.
19. Yoshida J, Ishimaru T, Fujimoto M, Hirata N, Matsubara N,
Koyanagi N. Risk factors for central venous catheter-related
bloodstream infection: a 1073-patient study. J Infect Chemother.
2008;14:399-403.
20. Dezfulian C, Lavelle J, Nallamothu BK, Kaufman SR, Saint S.
Rates of infection for single-lumen versus multilumen central
venous catheters: a meta-analysis. Crit Care Med.
2003;31:2385-2390.
21. Donnell SC, Taylor N, van Saene HK, Magnall VL, Pierro A,
Lloyd DA. Infection rates in surgical neonates and infants
receiving parenteral nutri-tion: a five-year prospective study. J
Hosp Infect. 2002;52:273-280.
22. Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD,
Abrams SA. High rates of mortality and morbidity occur in infants
with paren-teral nutritionassociated cholestasis. JPEN J Parenter
Enteral Nutr. 2010;34:32-37.
23. Fallon EM, Le HD, Puder M. Prevention of parenteral
nutrition-asso-ciated liver disease: role of -3 fish oil. Curr Opin
Organ Transplant. 2010;15:334-340.
24. Rangel SJ, Calkinsb CM, Cowlesc RA, et al. Parenteral
nutritionassociated cholestasis: an American Pediatric Surgical
Association Outcomes and Clinical Trials Committee systematic
review. J Pediatr Surg. 2012:47, 225-240.
25. Seida JC, Mager DR, Hartling L, Vandermeer B, Turner JM.
Parenteral -3 fatty acid lipid emulsions for children with
intestinal failure and other conditions: a systematic review. JPEN
J Parenter Enteral Nutr. 2013;37:44-55.
26. Barclay AR, Beattie LM, Weaver LT, Wilson DC. Systematic
review: medical and nutritional interventions for the management of
intestinal fail-ure and its resultant complications in children.
Aliment Pharmacol Ther. 2011;33:175-184.
27. Oxford Centre for Evidence-Based Medicine. Levels of
Evidence. March 2009. Available at:
http://www.cebm.net/index.aspx?o=1025. Accessed March 11, 2013.
28. Teitelbaum DH, Han-Markey T, Drongowski RA, et al. Use of
cholecys-tokinin to prevent the development of parenteral
nutrition-associated cho-lestasis. JPEN J Parenter Enteral Nutr.
1997;21:100-103.
29. Drongowski RA, Coran AG. An analysis of factors contributing
to the development of total parenteral nutrition-induced
cholestasis. JPEN J Parenter Enteral Nutr. 1989;13:586-589.
30. Slagle TA, Gross SJ. Effect of early low-volume enteral
substrate on subsequent feeding tolerance in very low birth weight
infants. J Pediatr. 1988;113:526-531.
31. Baserga MC, Sola A. Intrauterine growth restriction impacts
tolerance to total parenteral nutrition in extremely low birth
weight infants. J Perinatol. 2004;24:476-481.
32. Duro D, Mitchell PD, Kalish LA, et al. Risk factors for
parenteral nutri-tionassociated liver disease following surgical
therapy for necrotizing enterocolitis: A Glaser Pediatric Research
Network Study. J Pediatr Gastroenterol Nutr.
2011;52(5):595-600.
33. Brown MR, Thunberg BJ, Golub L, Maniscalco WM, Cox C,
Shapiro DL. Decreased cholestasis with enteral instead of
intravenous protein in the very low-birth-weight infant. J Pediatr
Gastroenterol Nutr. 1989;9:21-27.
34. Touloukian RJ, Seashore JH. Hepatic secretory obstruction
with total par-enteral nutrition in the infant. J Pediatr Surg.
1975;10:353-360.
35. Kubota A, Yonekura T, Hoki M, et al. Total parenteral
nutrition-associ-ated intrahepatic cholestasis in infants: 25 years
experience. J Pediatr Surg. 2000;35:1049-1051.
36. Vileisis RA, Inwood RJ, Hunt CE. Laboratory monitoring of
parenteral nutrition-associated hepatic dysfunction in infants.
JPEN J Parenter Enteral Nutr. 1981;5:67-69.
37. Beath SV, Davies P, Papadopoulou A, et al. Parenteral
nutrition-related cholestasis in postsurgical neonates:
multivariate analysis of risk factors. J Pediatr Surg.
1996;31:604-606.
38. Forchielli ML, Gura KM, Sandler R, Lo C. Aminosyn PF or
trophamine: which provides more protection from cholestasis
associated with total par-enteral nutrition? J Pediatr
Gastroenterol Nutr. 1995;21:374-382.
39. Jensen AR, Goldin AB, Koopmeiners JS, Stevens J, Waldhausen
JH, Kim SS. The association of cyclic parenteral nutrition and
decreased incidence of cholestatic liver disease in patients with
gastroschisis. J Pediatr Surg. 2009;44:183-189.
40. Nehra D, Fallon EM, Carlson SJ, et al. Provision of a
soy-based intrave-nous lipid emulsion at 1 g/kg/d does not prevent
cholestasis in neonates [published online ahead of print July 5,
2012]. JPEN J Parenter Enteral Nutr.
doi:10.1177/0148607112453072.
41. Farrell MK, Balistreri WF, Suchy FJ. Serum-sulfated
lithocholate as an indicator of cholestasis during parenteral
nutrition in infants and children. JPEN J Parenter Enteral Nutr.
1982;6:30-33.
42. Puntis JWL, Ball PA, Booth IW. Complications of neonatal
parenteral nutrition. Intensive Ther Clin Monitoring.
1987;8:48-56.
43. Fok TF, Chui KK, Cheung R, Ng PC, Cheung KL, Hjelm M.
Manganese intake and cholestatic jaundice in neonates receiving
parenteral nutrition: a randomized controlled study. Acta Paediatr.
2001;90:1009-1015.
44. Quirs-Tejeira RE, Ament ME, Reyen L, et al. Long-term
parenteral nutritional support and intestinal adaptation in
children with short bowel syndrome: a 25-year experience. J
Pediatr. 2004;145:157-163.
45. Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and
cholesta-sis in neonates with intestinal resection and long-term
parenteral nutrition. J Pediatr Gastroenterol Nutr.
1998;27:131-137.
46. Kglmeier J, Day C, Puntis JW. Clinical outcome in patients
from a single region who were dependent on parenteral nutrition for
28 days or more. Arch Dis Child. 2008;93:300-302.
47. Teitelbaum DH, Tracy TF Jr, Aouthmany MM, Llanos A, Brown
MB, Yu S, et al. Use of cholecystokinin-octapeptide for the
prevention of paren-teral nutrition-associated cholestasis.
Pediatrics. 2005;115:1332-1340.
48. Heubi JE, Wiechmann DA, Creutzinger V, Setchell KD, Squires
R Jr, Couser R, et al. Tauroursodeoxycholic acid (TUDCA) in the
preven-tion of total parenteral nutrition-associated liver disease.
J Pediatr. 2002;141:237-242.
49. Ng PC, Lee CH, Wong SPS, et al. High-dose oral erythromycin
decreased the incidence of parenteral nutrition-associated
cholestasis in preterm infants. Gastroenterology.
2007;132:1726-1739.
50. Ng YY, Su PH, Chen JY, et al. Efficacy of intermediate-dose
oral erythro-mycin on very low birth weight infants with feeding
intolerance. Pediatr Neonatol. 2012;53:34-40.
51. Kubota A, Okada A, Imura K, Kawahara H, Nezu R, Kamata S.
The effect of metronidazole on TPN-associated liver dysfunction in
neonates. J Pediatr Surg. 1990;25:618-621.
52. Salvador A, Janeczko M, Porat R, Sekhon R, Moewes A,
Schutzman D. Randomized controlled trial of early parenteral
nutrition cycling to pre-vent cholestasis in very low birth weight
infants. J Pediatr. 2012;161: 229-233.
53. Vileisis RA, Inwood RJ, Hunt CE. Prospective controlled
study of paren-teral nutrition-associated cholestatic jaundice:
effect of protein intake. J Pediatr. 1980;96:893-897.
54. Puder M, Valim C, Meisel JA, et al. Parenteral fish oil
improves outcomes in patients with parenteral nutrition-associated
liver injury. Ann Surg. 2009;250:395-402.
55. Gura KM, Lee S, Valim C, et al. Safety and efficacy of a
fish-oil-based fat emulsion in the treatment of parenteral
nutrition-associated liver disease. Pediatrics.
2008;121:e678-e686.
56. Lee SI, Valim C, Johnston P, et al. Impact of fish oil-based
lipid emulsion on serum triglyceride, bilirubin, and albumin levels
in children with par-enteral nutrition-associated liver disease.
Pediatr Res. 2009;66:698-703.
57. Goulet O, Joly F, Corriol O, Colomb-Jung V. Some new
insights in intes-tinal failure-associated liver disease. Curr Opin
Organ Transplantation. 2009;14:256-261.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
Lauriti et al 15
58. Beale EF, Nelson RM, Bucciarelli RL, Donnelly WH, Eitzman
DV. Intrahepatic cholestasis associated with parenteral nutrition
in premature infants. Pediatrics. 1979;64:342-347.
59. Sigalet D, Boctor D, Brindle M, Lam V, Robertson M. Elements
of suc-cessful intestinal rehabilitation. J Pediatr Surg.
2011;46:150-156.
60. Mazariegos GV, Superina R, Rudolph J, et al. Current status
of pediatric intestinal failure, rehabilitation, and
transplantation: summary of a col-loquium. Transplantation.
2011;92:1173-1180.
61. Avitzur Y, Grant D. Intestine transplantation in children:
update 2010. Pediatr Clin North Am. 2010;57:415-431.
62. Arslanoglu S, Moro GE, Tauschel HD, Boehm G. Ursodeoxycholic
acid treatment in preterm infants: a pilot study for the prevention
of cholestasis associated with total parenteral nutrition. J
Pediatr Gastroenterol Nutr. 2008;46:228-231.
63. Gokmen T, Oguz SS, Bozdag S, Erdeve O, Uras N, Dilmen U. A
con-trolled trial of erythromycin and UDCA in premature infants
during parenteral nutrition in minimizing feeding intolerance and
liver function abnormalities. J Perinatol. 2012;32(2):123-128.
64. Kaufman SS. Prevention of parenteral nutrition-associated
liver disease in children. Pediatr Transplant. 2002;6:37-42.
65. Lam HS, Ng PC. Use of prokinetics in the preterm infant.
Curr Opin Pediatr. 2011;23:156-160.
66. Ng PC. Use of oral erythromycin for the treatment of
gastrointestinal dys-motility in preterm infants. Neonatology.
2009;95:97-104.
67. Dunn L, Hulman S, Weiner J, Kliegman R. Beneficial effects
of early hypocaloric enteral feeding on neonatal gastrointestinal
function: prelimi-nary report of a randomized trial. J Pediatr.
1988;112:622-629.
68. Leaf A, Dorling J, Kempley S, et al. Early or delayed
enteral feeding for preterm growth-restricted infants: a randomized
trial. Pediatrics. 2012;129:e1260-e1268.
69. McClure RJ, Newell SJ. Randomised controlled study of
clinical out-come following trophic feeding. Arch Dis Child Fetal
Neonatal Ed. 2000;82:F29-F33.
70. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge
JA. Randomised controlled trial of an aggressive nutritional
regimen in sick very low birthweight infants. Arch Dis Child Fetal
Neonatal Ed. 1997;77:F4-F11.
71. Takehara H, Hino M, Kameoka K, Komi N. A new method of total
paren-teral nutrition for surgical neonates: it is possible that
cyclic TPN prevents intrahepatic cholestasis. Tokushima J Exp Med.
1990;37:97-102.
72. Sigalet D, Boctor D, Brindle M, Lam V, Robertson M. Elements
of suc-cessful intestinal rehabilitation. J Pediatr Surg.
2011;46:150-156.
73. Spencer AU, Yu S, Tracy TF, et al. Parenteral
nutritionassociated cho-lestasis in neonates: multivariate analysis
of the potential protective effect of taurine. JPEN J Parenter
Enteral Nutr. 2005;29:337-344.
74. Ong EG, Eaton S, Wade AM, et al. Randomized clinical trial
of gluta-mine-supplemented versus standard parenteral nutrition in
infants with surgical gastrointestinal disease. Br J Surg.
2012;99:929-938.
75. Duggan C, Stark AR, Auestad N, Collier S, Fulhan J, Gura K.
Glutamine supplementation in infants with gastrointestinal disease:
a randomized, placebo-controlled pilot trial. Nutrition.
2004;20:752-756.
76. Wang Y, Tao YX, Cai W, Tang QY, Feng Y, Wu J. Protective
effect of parenteral glutamine supplementation on hepatic function
in very low birth weight infants. Clin Nutr. 2010;29(3):307-311.
doi:10.1016/j.clnu.2010.03.009.
77. Lai H, Chen W. Effects of medium-chain and long-chain
triacylglycerols in pediatric surgical patients. Nutrition.
2000;16:401-406.
78. Tomsits E, Pataki M, Tlgyesi A, Fekete G, Rischak K, Szollr
L. Safety and efficacy of a lipid emulsion containing a mixture of
soybean oil, medium-chain triglycerides, olive oil, and fish oil: a
randomised, double-blind clinical trial in premature infants
requiring parenteral nutrition. J Pediatr Gastroenterol Nutr.
2010;51:514-521.
79. ClinicalTrials.gov, U.S. National Institutes of Health.
Preventing Cholestasis Using SMOFLipid. April 16, 2012. Available
at: http://clinicaltrials.gov/ct2/show/NCT01585935. Accessed March
8, 2013.
80. ClinicalTrials.gov, U.S. National Institutes of Health. Can
SMOFlipid, a Composite Parenteral Nutrition Lipid Emulsion, Prevent
Progression of Parenteral Nutrition Associated Liver Disease in
Infants? November 18, 2008. Available at:
http://clinicaltrials.gov/ct2/show/NCT00793195. Accessed March 8,
2013.
81. Nasr A, Diamond IR, de Silva NT, Wales PW. Is the use of
parenteral -3 lipid emulsions justified in surgical neonates with
mild parenteral nutritionassociated liver dysfunction? J Pediatr
Surg. 2010;45:980-986.
82. ClinicalTrials.gov, U.S. National Institutes of Health.
Cholestasis Prevention: Efficacy of IV Fish Oil. August 6, 2007.
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00512629.
Accessed March 8, 2013.
83. ClinicalTrials.gov, U.S. National Institutes of Health.
Ursodiol for Treating Parenteral Nutrition Associated Cholestasis
in Neonates. February 17, 2009. Available at:
http://clinicaltrials.gov/ct2/show/NCT00846963. Accessed March 8,
2013.
84. Cober MP, Killu G, Brattain A, Welch KB, Kunisaki SM,
Teitelbaum DH. Intravenous fat emulsions reduction for patients
with parenteral nutrition-associated liver disease. J Pediatr.
2012;160:421-427.
85. Cheung HM, Lam HS, Tam YH, Lee KH, Ng PC. Rescue treatment
of infants with intestinal failure and parenteral
nutrition-associated cholesta-sis (PNAC) using a parenteral
fish-oil-based lipid. Clin Nutr. 2009;28:209-212.
86. Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW.
Changing the paradigm: omegaven for the treatment of liver failure
in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr.
2009;48:209-215.
87. Rollins MD, Scaife ER, Jackson WD, Meyers RL, Mulroy CW,
Book LS. Elimination of soybean lipid emulsion in parenteral
nutrition and supple-mentation with enteral fish oil improve
cholestasis in infants with short bowel syndrome. Nutr Clin Pract.
2010;25:199-204.
88. Le HD, de Meijer VE, Zurakowski D, Meisel JA, Gura KM, Puder
M. Parenteral fish oil as monotherapy improves lipid profiles in
children with parenteral nutrition-associated liver disease. JPEN J
Parenter Enteral Nutr. 2010;34:477-484.
89. Diamond IR, de Silva NT, Tomlinson GA, et al. The role of
parenteral lipids in the development of advanced intestinal
failure-associated liver disease in infants: a multiple-variable
analysis. JPEN J Parenter Enteral Nutr. 2011;35:596-602.
90. Premkumar MH, Carter BA, Hawthorne KM, King K, Abrams SA.
High rates of resolution of cholestasis in parenteral
nutrition-associated liver disease with fish oil-based lipid
emulsion monotherapy. J Pediatr. 2013;162(4):793-798.
91. Le HD, de Meijer VE, Robinson EM, Zurakowski D, Potemkin AK,
Arsenault DA. Parenteral fish-oil-based lipid emulsion improves
fatty acid profiles and lipids in parenteral nutrition-dependent
children. Am J Clin Nutr. 2011;94(3):749-758.
92. Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD,
Abrams SA. High rates of mortality and morbidity occur in infants
with paren-teral nutrition associated cholestasis. JPEN J Parenter
Enteral Nutr. 2010;34:32-37.
93. ClinicalTrials.gov, U.S. National Institutes of Health.
Minimization of IntraLipid Versus Omegaven. November 23, 2010.
Available at: http://clinicaltrials.gov/ct2/show/NCT01247012.
Accessed March 8, 2013.
94. Goulet O, Antbi H, Wolf C, et al. A new intravenous fat
emulsion con-taining soybean oil, medium-chain triglycerides, olive
oil, and fish oil: a single-center, double-blind randomized study
on efficacy and safety in pediatric patients receiving home
parenteral nutrition. JPEN J Parenter Enteral Nutr.
2010;34:485-495.
95. De Marco G, Sordino D, Bruzzese E, et al. Early treatment
with urso-deoxycholic acid for cholestasis in children on
parenteral nutrition because of primary intestinal failure. Aliment
Pharmacol Ther. 2006;24: 387-394.
96. Spagnuolo MI, Iorio R, Vegnente A, Guarino A.
Ursodeoxycholic acid for treatment of cholestasis in children on
long-term total parenteral nutrition: a pilot study.
Gastroenterology. 1996;111:716-719.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/
-
16 Journal of Parenteral and Enteral Nutrition XX(X)
97. Al-Hathlol K, Al-Madani A, Al-Saif S, Abulaimoun B, Al-Tawil
K, El-Demerdash A. Ursodeoxycholic acid therapy for intractable
total par-enteral nutrition-associated cholestasis in surgical very
low birth weight infants. Singapore Med J. 2006;47:147-151.
98. Levine A, Maayan A, Shamir R, Dinari G, Sulkes J, Sirotta L.
Parenteral nutrition-associated cholestasis in preterm neonates:
evaluation of ursode-oxycholic acid treatment. J Pediatr Endocrinol
Metab. 1999;12:549-553.
99. Chen CY, Tsao PN, Chen HL, Chou HC, Hsieh WS, Chang MH.
Ursodeoxycholic acid (UDCA) therapy in very-low-birth-weight
infants with parenteral nutrition-associated cholestasis. J
Pediatr. 2004;145: 317-321.
100. Teitelbaum DH, Han-Markey T, Schumacher RE. Treatment of
paren-teral nutrition-associated cholestasis with
cholecystokinin-octapeptide. J Pediatr Surg. 1995;30:1082-1085.
101. Rintala RJ, Lindahl H, Pohjavuori M. Total parenteral
nutrition-asso-ciated cholestasis in surgical neonates may be
reversed by intrave-
nous cholecystokinin: a preliminary report. J Pediatr Surg.
1995;30: 827-830.
102. Javid PJ, Collier S, Richardson D, et al. The role of
enteral nutrition in the reversal of parenteral
nutrition-associated liver dysfunction in infants. J Pediatr Surg.
2005;40:1015-1018.
103. Cowles RA, Ventura KA, Martinez M, et al. Reversal of
intestinal failure-associated liver disease in infants and children
on parenteral nutrition: experience with 93 patients at a referral
center for intestinal rehabilitation. J Pediatr Surg.
2010;45:84-87.
104. Torres C, Sudan D, Vanderhoof J, et al. Role of an
intestinal rehabili-tation program in the treatment of advanced
intestinal failure. J Pediatr Gastroenterol Nutr.
2007;45:204-212.
105. Wales PW, Brindle M, Sauer CJ, Patel S, de Silva N, Chait
P. Percutaneous cholangiography for the treatment of parenteral
nutrition-associated cho-lestasis in surgical neonates: preliminary
experience. J Pediatr Surg. 2007;42:1913-1918.
at SYRACUSE UNIV LIBRARY on November 23,
2013pen.sagepub.comDownloaded from
http://pen.sagepub.com/http://pen.sagepub.com/