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Parenteral e Enteral - Nutrição
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http://pen.sagepub.com/Nutrition
Journal of Parenteral and Enteral
http://pen.sagepub.com/content/early/2014/03/31/0148607114527772The online version of this article can be found at:
DOI: 10.1177/0148607114527772 published online 2 April 2014JPEN J Parenter Enteral Nutr
Parenteral and Enteral Nutrition and Daniel TeitelbaumPaul W. Wales, Nancy Allen, Patricia Worthington, Donald George, Charlene Compher, the American Society for
Associated Liver DiseaseNutrition A.S.P.E.N. Clinical Guidelines: Support of Pediatric Patients With Intestinal Failure at Risk of Parenteral
- Jun 18, 2014version of this article was published on more recent A
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- Apr 2, 2014OnlineFirst Version of Record >>
- Jun 18, 2014Version of Record
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Journal of Parenteral and EnteralNutritionVolume XX Number X Month 201X 1 20 2014 American Societyfor Parenteral and Enteral NutritionDOI: 10.1177/0148607114527772jpen.sagepub.comhosted at online.sagepub.com
Clinical Guidelines
Background
Parenteral nutritionassociated liver disease (PNALD), also known as intestinal failureassociated liver disease (IFALD), is a feared and life-threatening complication associated with parenteral nutrition (PN) dependence. The incidence of short bowel syndrome in neonates is 24.5 per 100,000 live births with a case fatality rate of 37.5%.1 Two-thirds of patients with intestinal failure will develop PNALD, and traditionally, 25% would advance to end-stage liver disease. While the long-term survival is 70%90%,2-6 the prevention of PNALD stands to improve the quality of life of children and their families. There is no standardized definition of PNALD, and there is no agreed upon clinical threshold by which to make the diagnosis. PNALD is cholestatic in nature, and there is a spectrum of dis-ease moving from mild cholestasis through cirrhosis and liver failure with death unless transplantation is performed.6,7 For practical reasons, PNALD is most often described by hyper-bilirubinemia (direct or total). At other times, different liver biochemistry measures such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), -glutamyl transfer-ase (GGT), or alkaline phosphatase are used. When liver biop-sies have been used as an end point, they typically depict a
picture of cholestasis and varying degrees of fibrosis. Liver biopsy is invasive and not practical for routine care. It is also prone to sampling error.
PNALD is multifactorial and has been associated with PN. All components of PN may promote cholestasis. Most of the recent interest has been with soy-based fat emulsions (SOEs)
527772 PENXXX10.1177/0148607114527772Journal of Parenteral and Enteral NutritionWales et alresearch-article2014
From the 1Department of Surgery, University of Toronto, Toronto, Ontario, Canada; 2The Hospital for Sick Children, Toronto, Ontario, Canada; 3Childrens Mercy Hospital, Kansas City, Missouri; 4Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; 5Nemours Childrens Clinic, Jacksonville, Florida; 6University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania; and 7University of Michigan, Ann Arbor, Michigan.
Financial disclosure: None declared.
Received for publication February 21, 2014; accepted for publication February 21, 2014.
Corresponding Author:Charlene Compher, PhD, RD, CNSC, LDN, FADA, FASPEN, Professor of Nutrition Science, University of Pennsylvania School of Nursing, Claire M. Fagin Hall, 418 Curie Blvd, Philadelphia, PA 19104-4217, USA. Email: [email protected]
A.S.P.E.N. Clinical Guidelines: Support of Pediatric Patients With Intestinal Failure at Risk of Parenteral NutritionAssociated Liver Disease
Paul W. Wales, MD1,2; Nancy Allen, MLS, RD, CNSC3; Patricia Worthington, MSN, RN4; Donald George, MD5; Charlene Compher, PhD, RD, CNSC, LDN, FADA, FASPEN6; the American Society for Parenteral and Enteral Nutrition; and Daniel Teitelbaum, MD7
AbstractBackground: Children with severe intestinal failure and prolonged dependence on parenteral nutrition are susceptible to the development of parenteral nutritionassociated liver disease (PNALD). The purpose of this clinical guideline is to develop recommendations for the care of children with PN-dependent intestinal failure that have the potential to prevent PNALD or improve its treatment. Method: A systematic review of the best available evidence to answer a series of questions regarding clinical management of children with intestinal failure receiving parenteral or enteral nutrition was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the American Society for Parenteral and Enteral Nutrition Board of Directors. Questions: (1) Is ethanol lock effective in preventing bloodstream infection and catheter removal in children at risk of PNALD? (2) What fat emulsion strategies can be used in pediatric patients with intestinal failure to reduce the risk of or treat PNALD? (3) Can enteral ursodeoxycholic acid improve the treatment of PNALD in pediatric patients with intestinal failure? (4) Are PNALD outcomes improved when patients are managed by a multidisciplinary intestinal rehabilitation team? (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx)
Keywordspediatrics; life cycle; parenteral nutrition; nutrition; home nutrition support; lipids
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2 Journal of Parenteral and Enteral Nutrition XX(X)
available in North America. SOEs have been thought to pro-mote cholestasis as they contain predominantly -6 long-chain polyunsaturated fatty acids and phytosterols and have a rela-tively low antioxidant content.
Several clinical factors increase the risk of PNALD. Premature babies have increased risk for PNALD.7 Premature infants have immature livers with incompletely expressed enzymatic activity. There is also inadequate bile salt uptake and excretion, as well as inadequate production of glutathione. Recurrent sepsis, from bacterial translocation or related to cen-tral venous catheters, has been shown to be a risk factor for cholestasis. Endotoxin from sepsis acts directly or indirectly through production of inflammatory cytokines on bile trans-port proteins, impairing biliary excretion.8 Patients with intes-tinal failure commonly are unable to tolerate substantial enteral nutrient stimulation. Lack of enteral feeding impairs the enterohepatic circulation and bile acid secretion/absorption, thus leading to mucosal atrophy, and increases the risk of bac-terial translocation.
Since liver failure is the most common cause of death in patients with PNALD, the goal of therapy has been to optimize intestinal function and promote gut adaptation before the development of irreversible liver complications. With the con-trol of liver dysfunction, patients can be provided with a pro-longed period to allow intestinal adaptation to occur. Much of the improvement in patient outcomes over the past decade has been related to controlling the progression of PNALD. These guidelines focus on 4 therapeutic interventions of interest in the care of patients with intestinal failure.
Children with PN-dependent intestinal failure require cen-tral venous catheters to permit delivery of needed nutrients. These catheters are susceptible to catheter-related blood-stream infections (CLABSIs), which are associated with an increased risk of PNALD when they occur frequently.9,10 CLABSI is diagnosed when a common pathogen is cultured from both peripheral blood and the catheter. Children with intestinal failure are also at risk of these infections because they often have feeding enterostomies, stomas, and over-growth of intestinal bacteria that may result in translocation to the bloodstream.11 Thus, the prevention of CLABSI is one strategy that has been proposed to reduce the risk of PNALD. The instillation of 70% ethanol as a lock solution into the PN catheter has been examined as a strategy to prevent CLABSI.12 In laboratory studies, ethanol has been shown to be effective in penetrating and breaking down biofilm when the ethanol concentration was 30%; however, in vivo, the greatest effi-cacy has been shown with higher concentrations of ethanol (70%) with dwell times of 2 hours or more.13 Both silicone and polyurethane catheters have been tested in the laboratory, but only silicone catheters have been tested with ethanol lock therapy in children.11
Doses of intravenous (IV) SOE 1 g/kg/d have also been associated with increased risk of PNALD in mixed adult and pediatric home PN (HPN) cohorts14 and examined more
recently in children.15,16 Young children with PN, however, require a larger dose of fat emulsion per kilogram body weight to provide for their energy requirements to promote growth, provide neurological development, and prevent essential fatty acid deficiency (EFAD). Reduced doses of SOE, the addition of fish oil emulsion (FOE), and fat emulsions designed with a mixture of soy oil, medium-chain triglycerides, olive oil, and fish oil (SMOF) have been considered as potential therapies in children with HPN who develop PNALD.
Ursodeoxycholic acid (UDCA) is a bile acid that has been given orally to treat cholestatic liver disease in adults.17 While the mechanism of UDCAs effects is not fully established, the treatment may correct bile acid deficiency, improve bile flow, displace cytotoxic bile acids, or provide immunomodulatory protection.17 However, less is known about such treatment in children, particularly in children with PN-dependent intestinal failure as absorption of UDCA may be limited.
Over the past few years, multidisciplinary nutrition support teams or intestinal rehabilitation programs have been devel-oped to optimize the management of children with intestinal failure who require HPN. The impact of these programs on PNALD outcomes has been examined.
The purpose of this clinical guideline is to develop recom-mendations for the care of children with PN-dependent intesti-nal failure that have the potential to prevent PNALD or improve its treatment.
Method
The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is an organization composed of healthcare profes-sionals representing the disciplines of medicine, nursing, phar-macy, dietetics, and nutrition science. The mission of A.S.P.E.N. is to improve patient care by advancing the science and practice of clinical nutrition and metabolism. A.S.P.E.N. vigorously works to support quality patient care, education, and research in the fields of nutrition and metabolic support in all healthcare settings. These Clinical Guidelines were devel-oped under the guidance of the A.S.P.E.N. Board of Directors. Promotion of safe and effective patient care by nutrition sup-port practitioners is a critical role of the A.S.P.E.N. organiza-tion. The A.S.P.E.N. Board of Directors has been publishing Clinical Guidelines since 1986.18-28
These A.S.P.E.N. Clinical Guidelines are based on general conclusions of health professionals who, in developing such guidelines, have balanced potential benefits to be derived from a particular mode of medical therapy against certain risks inherent with such therapy. However, the professional judg-ment of the attending health professional is the primary com-ponent of quality medical care. Since guidelines cannot account for every variation in circumstances, the practitioner must always exercise professional judgment in their application. These Clinical Guidelines are intended to supplement, but not replace, professional training and judgment.
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Wales et al 3
The A.S.P.E.N. Clinical Guidelines process has adopted con-cepts of the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group.29-32 A full description of the methodology has been published.33 Briefly, specific clinical questions where nutrition support is a relevant mode of therapy are developed and key clinical out-comes are identified. A rigorous search of the published litera-ture is conducted, and each included study is assessed for research quality, tables of findings are developed, and the body of evidence for the question is evaluated. A recommendation for clinical practice that is based on both the best available evidence and the risks and benefits to patients is developed by consensus. Strong recommendations are made when the evidence is graded high and/or net benefits outweigh harms. Weak recommenda-tions are made when evidence is graded low or if there are important trade-offs to the patient. When limited research is available to answer a question, no recommendation can be made.
A.S.P.E.N. Clinical Guidelines undergo peer review by clinical content experts both internal and external to the orga-nization. The author and reviewer teams for this guideline include members of each of the professional groups that could play a role in the use of such a guideline (dietetics, nursing, medicine, pharmacy, research), as well as by the A.S.P.E.N. Board of Directors. After the author response to the initial reviews, the guideline was reviewed and approved by the A.S.P.E.N. Board of Directors and their legal consultant.
Results
Four questions were developed to be addressed by this guide-line. The questions and recommendations are summarized in Table 1. For the current Clinical Guideline, the following terms were used to search PubMed and CINAHL until May 2013: intestinal failure, short bowel syndrome, clinical outcomes, lipid, bloodstream infection, team, multidisciplinary team, par-enteral nutrition, and enteral nutrition. The searches were lim-ited to studies that included pediatric subjects, English-language publications, randomized controlled trials (RCTs), controlled observational studies, and uncontrolled case series. A total of 16 RCTs, 13 controlled observational studies, and 23 uncontrolled case series met the inclusion criteria and were abstracted for the tables below. A revision of this guideline is planned for 2018.
Question 1. Is ethanol lock effective in preventing blood-stream infection and catheter removal in children at risk of PNALD? (Tables 2, 3)
Recommendation: A suggestion is made to use ethanol lock to prevent CLABSI and to reduce catheter replacements in children at risk of PNALD.
Evidence: Low and very lowRecommendation Grade: WeakRationale: The evidence for decreased CLABSI and cathe-
ter removal is low and very low, respectively. The desirable
effect of both decreased infection and catheter removal has to be interpreted in light of the unknown effects of increased thrombus formation and disruption of catheter structure integrity.
The Oliveira et al34 meta-analysis of observational studies that are summarized in Table 2 includes low-quality evidence that shows a very strong association favoring of the use of eth-anol lock for the prevention of CLABSI. However, the size of the study cohort is very small. Further research is likely to change the estimate of the effect.
Catheter replacement was not a primary outcome of the included studies. The desirable effect of decreased catheter replacement has to be interpreted in light of the unknown effects of increased thrombus formation and disruption of cath-eter structure integrity.35 The Oliveira et al34 meta-analysis of observational studies includes low-quality evidence that shows a strong association with the use of ethanol lock and the reduc-tion of catheter replacements. However, one of the included studies reports the superiority of heparin lock to decrease cath-eter replacements. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
No recommendation can be made regarding the risk of cath-eter thrombosis due to ethanol lock therapy secondary to small sample sizes in observational studies, variable days of lock therapy, broad differences in observation time, and lack of clar-ity about the procedure with regard to ethanol concentration and withdrawal vs instillation of the ethanol solution after the dwell time. All research reports, however, were in cohorts of HPN patients. Further research is likely to change our confi-dence in the risk of catheter thrombosis with regard to ethanol lock.
Research is needed in a number of key areas. Data are needed to define more clearly the most effective concentration of ethanol in the lock, the number of days per week and the optimum duration of instillation of flush, and whether the best practice is flushing the ethanol through the catheter or with-drawing it after the instillation time. Whether silicone catheters are the only ones that should be used for ethanol lock is also important to consider systematically. Future clinical trials that use thrombosis and maintenance of catheter structural integrity as outcomes are needed and might change our confidence in the efficacy of this therapy.36
Question 2. What fat emulsion strategies can be used in pediatric patients with intestinal failure to reduce the risk of or treat PNALD? (Tables 4, 5)
Recommendation: Since the only IV fat emulsion available for use in the United States is SOE, a suggestion is made to reduce the dose of SOE to 1 g/kg/d to treat cholestasis in chil-dren with PNALD. The quality of evidence supporting this rec-ommendation is very low. Most studies are small observational studies. The desirable effect of reduction of liver indices has to
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4 Journal of Parenteral and Enteral Nutrition XX(X)
be considered in light of the unknown effects of poor growth and development when lipids are restricted.
Evidence: Very LowRecommendation Grade: Weak
FOE is available in the United States under a compassionate use protocol. Until it is approved by the U.S. Food and Drug
Administration (FDA), no recommendation can be made for use in the United States. The evidence supporting the use of FOE is very low quality. Included studies are small observational studies that are confounded by concurrent lipid dose reduction and advancement of enteral feedings. The desirable effect of improved cholestasis has to be considered in light of the unknown effects of poor growth and development when lipids are restricted.
Table 1. Nutrition Support Clinical Guideline Recommendations in Pediatric Patients With Intestinal Failure.
Question Recommendation Grade
1. Is ethanol lock effective in preventing bloodstream infection and catheter removal in children at risk of parenteral nutritionassociated liver disease (PNALD)?
A suggestion is made to use ethanol lock to prevent catheter-related bloodstream infection (CLABSI) and to reduce catheter replacements in children at risk of PNALD. The evidence for decreased CLABSI and catheter removal is low and very low, respectively. The desirable effect of both decreased infection and catheter removal has to be interpreted in light of the unknown effects of increased thrombus formation and disruption of catheter structure integrity.
Evidence: Low, very lowRecommendation: Weak
2. What fat emulsion strategies can be used in pediatric patients with intestinal failure to reduce the risk of or treat PNALD?
Since the only fat emulsion in the United States is soy oil fat emulsion (SOE), a suggestion is made to reduce the dose of SOE to 1 g/kg/d to treat cholestasis in children with PNALD. The quality of evidence supporting this recommendation is very low. Most studies are small observational studies. The desirable effect of the reduction of liver indices has to be considered in light of the unknown effects of poor growth and development when lipids are restricted.
Evidence: Very lowRecommendation: Weak
Fish oil fat emulsion (FOE) is available in the United States under a compassionate use protocol. Until it is approved by the Food and Drug Administration, no recommendation can be made for use in the United States. The evidence supporting the use of FOE is very low quality. Included studies are small observational studies that are confounded by concurrent SOE dose reduction and advancement of enteral feedings. The desirable effect of the reduction of liver indices has to be considered in light of the unknown effects of poor growth and development when lipids are restricted.
Evidence: Further research needed
Recommendation: No recommendation
Fat emulsion with soy oil, medium-chain triglycerides, olive oil, and fish oil (SMOF) is not available in the United States. Until it is approved for use, no recommendation can be made for use in the United States. If available, the evidence supporting the use of SMOF for the treatment of cholestasis is very low quality. The randomized controlled trials are primarily safety and efficacy studies in preterm infants with the primary outcome variable of plasma phospholipid levels and safety.
Evidence: Further research needed
Recommendation: No recommendation
Fat emulsion that contains a blend of refined olive and soy oil has been approved for adults receiving PN. It is not approved for infants or children. Until it is approved for use in children, no recommendation can be made for use in the United States.
Evidence: Further research needed
Recommendation: No recommendation
3. Can enteral ursodeoxycholic acid (UDCA) improve the treatment of PNALD in pediatric patients with intestinal failure?
A suggestion is made to use UDCA for the treatment of elevated liver enzymes in children with PNALD. The evidence is of very low quality and is confounded by the presence of enteral feedings along with treatment with UDCA. In the included studies, no harm from this treatment was reported. The desirable effect of the reduction of liver indices has to be weighed against the unknown efficacy of the treatment and the fact that in most cases, the study participants did not have primary intestinal pathology.
Evidence: Very lowRecommendation: Weak
4. Are PNALD outcomes improved when patients are managed by a multidisciplinary intestinal rehabilitation team?
A suggestion is made to refer patients with PN-dependent intestinal failure to multidisciplinary intestinal rehabilitation programs. The evidence on this topic is of very low quality, but the improvement in survival is compelling, and the risk to the child of treatment with multidisciplinary practice is not increased.
Evidence: Very lowRecommendation: Weak
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5Tab
le 2
. E
vid
ence
Su
mm
ary
Qu
esti
on 1
: Is
Eth
anol
Loc
k E
ffec
tive
in P
reve
ntin
g B
lood
stre
am I
nfec
tion
and
Cat
hete
r R
emov
al in
Chi
ldre
n at
Ris
k of
PN
AL
D?
Aut
hor,
Yea
r,
Ref
eren
ce N
o.S
tudy
Des
ign,
Q
uali
tyP
opul
atio
n, S
etti
ng, N
Stu
dy O
bjec
tive
Res
ults
Com
men
ts
Eth
anol
Loc
k S
olu
tion
Pie
roni
, 201
353
Ret
rosp
ecti
ve
case
ser
ies
HP
N p
atie
nts,
N =
14
Ass
ess
CL
AB
SI
prio
r
to a
nd a
fter
70%
et
hano
l loc
k th
erap
y ov
er 2
hou
rs o
nce
wee
kly
Pri
or t
o et
han
ol lo
ck:
CL
AB
SI
= 9
.8/1
000
CV
C d
ays
CV
C r
emov
al =
4.3
/100
0 C
VC
day
sD
uri
ng
eth
anol
lock
: C
LA
BS
I =
2.7
/100
0 C
VC
day
sC
VC
rem
oval
= 1
/100
0 C
VC
day
sN
o C
VC
thro
mbo
sis
afte
r 69
0 da
ys o
f ob
serv
atio
nO
ne c
ase
of f
acia
l flu
shin
g th
at r
esol
ved
wit
h re
duce
d
volu
me
of lo
ck
Tot
al o
f 87
CL
AB
SIs
th
roug
h en
tire
tim
e,
803
pree
than
ol lo
ck +
69
0 po
stet
hano
l loc
k ca
thet
er d
ays
Won
g et
al,
2012
54R
etro
spec
tive
ca
se s
erie
sH
PN
pat
ient
s, N
= 4
Rep
ort c
ase
seri
es o
f ca
thet
er c
ompl
icat
ions
af
ter
use
of 7
0% e
than
ol
lock
3 ti
mes
wee
kly
Thr
ombo
sis
in li
ne w
hen
etha
nol w
ithd
raw
n at
413
day
s
(n =
1),
at 1
68 d
ays
(n =
1),
at 9
day
s (n
= 1
), a
nd C
VC
oc
clus
ion
at 3
day
s (n
= 1
). T
he o
cclu
sion
cle
ared
aft
er
stop
ping
eth
anol
lock
.
Wal
es e
t al,
2011
55R
etro
spec
tive
ca
se s
erie
sH
PN
pat
ient
s w
ith
at le
ast 1
pr
evio
us C
LA
BS
I.N
= 1
0M
edia
n ag
e 44
mon
ths
(ran
ge,
311
29 m
onth
s)B
ody
wei
ght:
5 kg
for
sin
gle
lum
en;
9 kg
for
dou
ble-
lum
en C
VC
Ass
ess
inci
denc
e of
C
LA
BS
I an
d C
VC
re
plac
emen
ts a
fter
in
itia
tion
of
70%
et
hano
l loc
k th
erap
y da
ily
Wit
h et
hano
l loc
k, C
LA
BS
I fe
ll f
rom
10.
2
6.2
to 0
.9
1.
8/10
00 C
VC
day
s (P
= .0
05)
CV
C r
epla
cem
ents
fel
l fro
m 5
.6 to
0.3
/100
0 C
VC
day
s
(P =
.038
)E
than
ol lo
ck d
isco
ntin
ued
in 2
of
10 p
atie
nts
due
to C
VC
th
rom
bosi
s, o
ccur
red
227
64
day
s af
ter
lock
sta
rted
Sm
all s
ampl
e si
zeM
inim
um d
wel
l tim
e
4 ho
urs
Cob
er e
t al,
2011
15R
etro
spec
tive
ca
se s
erie
sH
PN
pat
ient
s w
ith
sili
cone
-bas
ed
CV
C, w
eigh
t 5
kg, h
igh
risk
fo
r C
LA
BS
I (>
2 C
VC
rep
lace
d du
e to
CL
AB
SI,
2 C
LA
BS
Is n
ot
clea
red,
loss
of
CV
C a
cces
s si
tes)
N =
15
Mea
n ag
e: 5
.6
6.9
yea
rsM
ean
wei
ght:
19.
9 kg
Eva
luat
e ou
tcom
es
of o
utpa
tien
t dai
ly
etha
nol l
ock
ther
apy
on C
LA
BS
I in
cide
nce,
ty
pes
of o
rgan
ism
s, a
nd
com
plic
atio
ns o
f da
ily
etha
nol l
ock
ther
apy
Wit
h et
hano
l loc
k, m
ean
CL
AB
SI
fell
fro
m 8
.0
5.4
to
1.3
3.
0/10
00 C
VC
day
s (P
< .0
1)F
our
pati
ents
exp
erie
nced
5 e
piso
des
of C
LA
BS
I w
ith
Stap
hylo
cocc
us s
peci
esA
dver
se e
vent
s in
clud
ed d
eep
vein
thro
mbo
sis
(n =
1),
CV
C
occl
usio
n (n
= 3
), a
nd r
epai
r of
CV
C f
or le
akag
e/te
ar (
n =
20)
Adv
erse
eve
nts
rose
fro
m 3
.1
5.2
to 6
.4
10.
0/10
00 C
VC
da
ys (
P =
.20)
Sm
all s
ampl
e si
zeM
inim
um d
wel
l tim
e 2
hour
sE
than
ol w
ithd
raw
n an
d di
scar
ded
at th
e en
d of
dw
ell t
ime
Jone
s et
al,
2010
56
Ret
rosp
ecti
ve
case
ser
ies
HP
N p
atie
nts
aged
3 m
onth
s to
18
year
s, w
eigh
t >5
kg, w
ith
at le
ast
1 pr
ior
CL
AB
SI
in s
ilic
one-
base
d C
VC
or
PIC
CN
= 2
3
Ass
ess
inci
denc
e of
C
LA
BS
I af
ter
70%
et
hano
l loc
k 3
tim
es
wee
kly
CL
AB
SI
decr
ease
d fr
om m
edia
n (I
QR
) of
9.9
(4.
416
) to
2.
1 (0
4.7
)/10
00 C
VC
day
s, P
= .0
3E
ight
een
of 2
3 pa
tien
ts h
ad d
ecre
ased
CL
AB
SI
rate
; 5 o
f 23
(p
atie
nts
wit
h m
otil
ity
diso
rder
s) h
ad in
crea
sed
rate
No
adve
rse
even
ts o
ver
22 m
onth
s
Mou
w e
t al,
2008
57R
etro
spec
tive
ca
se s
erie
sH
PN
pat
ient
s w
ith
sili
cone
-bas
ed
CV
C, N
= 1
0E
valu
ate
inci
denc
e ra
tes
of C
LA
BS
I, C
VC
re
mov
al, a
nd a
dver
se
even
ts a
fter
dai
ly 7
0%
etha
nol l
ock
ther
apy
Ten
pat
ient
s ha
d 26
CV
C, 3
556
tota
l CV
C d
ays,
30
18 e
than
ol lo
ck d
ays
CL
AB
SI
in 5
pat
ient
s de
crea
sed
from
11.
4 to
2.0
7/10
00
CV
C d
ays
CL
AB
SI
rate
for
pat
ient
s w
ith
no e
than
ol-l
ock
free
per
iod
(n
= 5
) w
as 1
.99/
1000
cat
hete
r da
ysC
VC
thro
mbo
sis
afte
r 63
0 da
ys o
f lo
ck th
erap
y, n
= 1
Dis
sem
inat
ed in
trav
ascu
lar
coag
ulat
ion,
2 e
vent
s in
1 p
atie
nt
No
stat
isti
cal a
naly
sis
due
to s
mal
l sam
ple
size
Dw
ell t
ime
414
hou
rsE
than
ol in
stil
led
thro
ugh
the
cath
eter
lum
en a
t th
e en
d of
dw
ell t
ime
CL
AB
SI,
cat
hete
r-re
late
d bl
oods
trea
m in
fect
ion;
CV
C, c
entr
al v
enou
s ca
thet
er; H
PN
, hom
e pa
rent
eral
nut
riti
on; I
QR
, int
erqu
arti
le r
ange
; PIC
C, p
erip
hera
lly
inse
rted
cen
tral
cat
hete
r; P
NA
LD
, par
ente
ral
nutr
itio
nas
soci
ated
live
r di
seas
e.
by guest on July 11, 2014pen.sagepub.comDownloaded from
6
Tab
le 3
. G
RA
DE
Tab
le Q
ues
tion
1:
Is E
than
ol L
ock
Eff
ecti
ve in
Pre
vent
ing
Blo
odst
ream
Inf
ecti
on a
nd C
athe
ter
Rem
oval
in C
hild
ren
at R
isk
of P
NA
LD
?
Qua
lity
Ass
essm
ent
No.
of
Pat
ient
sE
ffec
t
Qua
lity
Impo
rtan
ce
No.
of
Stu
dies
Des
ign
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nE
than
ol
Loc
ksH
epar
in
Loc
ksR
elat
ive
(95%
CI)
Abs
olut
e
CR
BS
I ra
te (
foll
ow-u
p 2
153
018
day
s; m
easu
red
wit
h a
vera
ge r
ate
per
100
0 ca
thet
er d
ays;
ran
ge o
f sc
ores
, 6.7
9.3
; b
ette
r in
dic
ated
by
low
er v
alu
es)
4O
bser
vati
onal
st
udie
sN
o se
riou
s ri
sk o
f bi
asa
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
n0b
MD
7.4
6 hi
gher
(5
.87
9.47
hig
her)
Low
Cri
tica
l
Cat
het
er r
epla
cem
ent
(fol
low
-up
215
301
8 d
ays;
mea
sure
d w
ith
ave
rage
rat
e p
er 1
000
cath
eter
day
s; r
ange
of
scor
es,
1.46
to
8.2;
bet
ter
ind
icat
ed b
y h
igh
er v
alu
es)
3O
bser
vati
onal
st
udie
sN
o se
riou
s ri
sk o
f bi
asa,
c
Ser
ious
dN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
n03
MD
5.0
7 hi
gher
(1
.12
9.03
hig
her)
Low
Cri
tica
l
CI,
con
fide
nce
inte
rval
; CL
AB
SI,
cat
hete
r-re
late
d bl
oods
trea
m in
fect
ion;
MD
, mea
n di
ffer
ence
; PN
AL
D, p
aren
tera
l nut
riti
ona
ssoc
iate
d li
ver
dise
ase.
a Use
d th
e N
ewca
stle
-Ott
awa
scal
e fo
r co
hort
stu
dies
.b T
he n
umbe
r of
par
tici
pant
s in
eit
her
the
inte
rven
tion
or
cont
rol g
roup
was
pro
vide
d in
the
met
a-an
alys
is.
c Tw
o cr
iter
ia f
or b
ias
wer
e no
t rep
orte
d or
met
in a
ll s
tudi
es. I
t was
not
rep
orte
d if
the
outc
ome
of in
tere
st w
as a
bsen
t at t
he s
tart
of
the
stud
y, a
nd 1
stu
dy p
oorl
y re
port
ed a
des
crip
tion
of
excl
uded
pa
tien
ts. T
he o
ther
3 s
tudi
es d
id n
ot r
epor
t on
excl
uded
pat
ient
s.d M
ouw
et a
l57
favo
red
hepa
rin
lock
, whi
le th
e ot
her
2 st
udie
s fa
vore
d et
hano
l loc
ks. H
eter
ogen
eity
is h
igh;
the
I2 s
tati
stic
= 7
0%.
by guest on July 11, 2014pen.sagepub.comDownloaded from
7Tab
le 4
. E
vid
ence
Su
mm
ary
Qu
esti
on 2
: W
hat F
at E
mul
sion
Str
ateg
ies
Can
Be
Use
d in
Ped
iatr
ic P
atie
nts
Wit
h In
test
inal
Fai
lure
to R
educ
e th
e R
isk
of o
r T
reat
PN
AL
D?
Aut
hor,
Yea
r,
Ref
eren
ce N
o.S
tudy
Des
ign,
Q
uali
tyP
opul
atio
n, S
etti
ng, N
Stu
dy O
bjec
tive
Res
ults
Com
men
ts
Soy
Fat
Em
uls
ion
Dos
e
Rol
lins
et a
l, 20
1316
RC
T
pilo
tIn
fant
s 2
6 w
eeks
ge
stat
ion
wit
h >
50%
dai
ly e
nerg
y in
take
fro
m
PN
for
at l
east
4 w
eeks
SO
E 1
g/k
g/d
wit
h m
ean
GIR
at
10.7
mg/
kg/m
in, n
= 1
5S
OE
3 g
/kg/
d w
ith
mea
n G
IR a
t 8.
8 m
g/kg
/min
, n =
13
N =
28
Dem
onst
rate
the
feas
ibil
ity
of
perf
orm
ing
a st
udy
to
com
pare
red
uced
dos
e (1
g/k
g/d)
vs
stan
dard
do
se (
3 g/
kg/d
) of
S
OE
Con
juga
ted
bil
iru
bin
(ch
ange
fro
m b
asel
ine)
:0vs1.3m
g/dL
,1vs3g/kg/d,P
= .0
4N
o di
ffer
ence
in A
LT
, AS
T, G
GT
, alk
alin
e ph
osph
atas
eT
rien
e to
tet
raen
e ra
tio:
0.0160.004vs0.0120.002,1vs3g/kg/d,P
= .0
3W
eigh
t z
scor
e (c
han
ge f
rom
bas
elin
e):
0.36vs0.01,1vs3g/kg/d,P
= .0
06H
ead
cir
cum
fere
nce
z s
core
(ch
ange
fro
m
bas
elin
e):
0.05vs+0.005,1vs3g/kg/d,P
= .0
9
Cho
lest
asis
mar
kers
ro
se le
ss r
apid
ly, n
o E
FA
D, l
ess
grow
th,
and
tren
d to
low
er h
ead
circ
umfe
renc
e w
ith
1 g/
kg/d
Neh
ra e
t al,
2013
58R
etro
spec
tive
re
view
of
case
ser
ies
All
neo
nate
s ad
mit
ted
to I
CU
20
072
011
wit
h su
rgic
al
cond
itio
n ne
cess
itat
ing
PN
su
ppor
t for
21
day
sP
atie
nts
wit
h S
OE
at 1
g/k
g/d,
n
= 2
9P
atie
nts
wit
h S
OE
at 2
3 g
/kg/
d,
n =
32
N =
53
Det
erm
ine
whe
ther
pr
ovis
ion
of S
OE
at
1 g
/kg/
d pr
even
ts
the
deve
lopm
ent o
f ch
oles
tasi
sC
ompa
re in
cide
nce
of c
hole
stas
is in
ne
onat
es w
ith
SO
E a
t 1
g/kg
/d w
ith
thos
e w
ith
23
g/kg
/d
No
diff
eren
ce in
con
juga
ted
or u
ncon
juga
ted
bili
rubi
n, A
LT
, or
alka
line
pho
spha
tase
at b
asel
ine
by S
OE
dos
e gr
oup
Inci
den
ce o
f ch
oles
tasi
s:1 g/kg/d,51.7%
23g/kg/d,43.8%
,notsignificantlydifferent
Tim
e to
ch
oles
tasi
s:1 g/kg/d,32.624.1d
23 g/kg/d,27.710.6d,notsignificantlydifferent
Sm
all s
ampl
eR
etro
spec
tive
dat
a w
ith
no in
form
atio
n ab
out
why
som
e pa
tien
ts
wer
e se
lect
ed f
or 1
-g/
kg/d
dos
ing
Cob
er e
t al 2
0124
1P
rosp
ecti
ve
cont
roll
ed
coho
rt
obse
rvat
ion
Sur
gica
l pat
ient
s w
ith
chro
nic
PN
(
2 w
eeks
) ty
pica
lly
prov
idin
g S
OE
3 g
/kg/
d an
d w
ith
chol
esta
sis
(con
juga
ted
bili
rubi
n 2
.5 m
g/dL
); S
OE
, n =
31
Dos
e re
duce
d to
1 g
/kg/
d S
OE
, n
= 3
1
Eva
luat
e ef
fica
cy o
f re
duce
d S
OE
dos
e on
bil
irub
in le
vels
, gr
owth
, inc
iden
ce o
f E
FA
def
icie
ncy,
and
m
orta
lity
Tot
al b
ilir
ub
in c
han
ge f
rom
bas
elin
e:SOE=0.39mg/dL
/wk,P
= .0
27Dose-reducedSOE=0.73m
g/dL
/wk,P
= .0
09Dosereduced,controlledforsepticepisodes,slope
=
0.09
mg/
dL/d
, P =
.049
Gro
wth
, con
trol
vs
dos
e re
du
ced
:Weightg
ain=13.2513.81gvs13.5512.38g
Weight-for-lengthz
sco
res
=
0.89
1
.38
vs
0.6
1
.52
Headcircum
ference
z sc
ores
=
0.99
0
.22
vs
0.6
4
1.26
EF
AD
:Mild deficiencyin
8of13dose-reducedpatients
No severeorclinicaldeficiencysigns
Dro
p in
bil
irub
in w
ith
no
diff
eren
ce in
gro
wth
pa
ram
eter
s
Dia
mon
d et
al,
2011
9R
etro
spec
tive
re
view
of
case
ser
ies
All
infa
nts
wit
h ga
stro
inte
stin
al
surg
ery
and
PN
, N =
152
; in
clud
ing
22 w
ith
incr
ease
d co
njug
ated
bil
irub
in
Ana
lysi
s of
fac
tors
as
soci
ated
wit
h in
crea
sed
conj
ugat
ed
bili
rubi
n
Day
s of
SO
E >
2.5
g/kg
/d a
ssoc
iate
d w
ith
elev
ated
bi
liru
bin
Num
ber
of s
epti
c ep
isod
es, d
ays
wit
h am
ino
acid
>2.
5 g/
kg/d
al
so p
redi
ct e
leva
ted
bili
rubi
n
(con
tinu
ed)
by guest on July 11, 2014pen.sagepub.comDownloaded from
8
Aut
hor,
Yea
r,
Ref
eren
ce N
o.S
tudy
Des
ign,
Q
uali
tyP
opul
atio
n, S
etti
ng, N
Stu
dy O
bjec
tive
Res
ults
Com
men
ts
Rol
lins
et a
l, 20
1039
Ret
rosp
ecti
ve
revi
ew o
f ca
se s
erie
s
Infa
nts
wit
h sh
ort b
owel
syn
drom
e an
d P
N f
or a
t lea
st 6
mon
ths
du
rati
on, N
= 2
6
Is e
lim
inat
ion
of S
OE
as
soci
ated
wit
h de
crea
se in
cho
lest
asis
in
indi
vidu
al p
atie
nts?
Tw
enty
-thr
ee o
f 26
dev
elop
ed c
hole
stas
isE
lim
inat
ion
of S
OE
in 6
pat
ient
s re
solv
ed c
hole
stas
isS
mal
l sam
ple
Ent
eral
fis
h oi
l pro
vide
d to
4 p
atie
nts
Shi
n et
al,
2008
40R
etro
spec
tive
re
view
of
case
ser
ies
Low
-bir
th-w
eigh
t neo
nate
s w
ith
PN
:W
ith
chol
esta
sis,
n =
22
Wit
hout
cho
lest
asis
, n =
22
Def
ine
fact
ors
asso
ciat
ed w
ith
chol
esta
sis
Cum
ulat
ive
SO
E d
ose-
inde
pend
ent r
isk
fact
or f
or
chol
esta
sis:
OR
, 1.1
7 (9
5% C
I, 1
.007
1.3
69,
P =
.041
)
Day
s w
ith
no E
N,
pare
nter
al a
min
o ac
id
dose
, day
s on
ant
ibio
tics
al
so a
ssoc
iate
d
Col
omb
et a
l, 20
0038
Ret
rosp
ecti
ve
revi
ew o
f ca
se s
erie
s
Chi
ldre
n in
HP
N p
rogr
am
1989
199
9, to
tal N
= 1
83C
hild
ren
wit
h ch
oles
tasi
s, n
= 1
0 w
ith
23 e
piso
des
of c
hole
stas
is
Eva
luat
e ro
le S
OE
in
cho
lest
asis
de
velo
pmen
t
Tot
al b
ilir
ub
in:
50330mol/L
Liv
er b
iop
sy:
In
9 c
hild
ren,
all
abn
orm
al w
ith
vari
ed le
vels
of
fibr
osis
and
cho
lest
asis
, no
cirr
hosi
sL
ipid
dos
e:In15of23episodesofcholestasis,lipiddosehad
been
incr
ease
d fr
om 0
.94
0.
89 to
2.2
0
.41
g/kg
/dIn17of23episodeswherelipiddosewasstopped,
tota
l bil
irub
in d
ropp
ed w
ithi
n 1
3 m
onth
sEssentialfattyaciddeficiencyin
3children
mea
sure
d af
ter
3 m
onth
s w
itho
ut f
at e
mul
sion
Cholestasisepisodesoccurred5.73.8yearsafter
PN
init
iati
on
Aut
hors
pro
pose
gu
idel
ines
of:
Maxim
aldailySOE
22.
5 g/
kg/d
, wit
h m
axim
al in
fusi
on r
ate
of
150
mg/
kg/h
, no
mor
e th
an 5
infu
sion
s w
eekl
y,
and
max
imal
lipi
d-to
-en
ergy
rat
io o
f 25
%Monitorliverfunction
test
s an
d pl
atel
ets
FO
E v
s S
OE
Fat
Em
uls
ion
Cal
kins
et a
l, 20
1359
Pro
spec
tive
ob
serv
atio
n of
cas
e se
ries
Chi
ldre
n ag
es 2
wee
ks to
18
year
s w
ith
PN
AL
D o
n S
OE
n =
10
pati
ents
trea
ted
wit
h F
OE
at
1 g
/kg/
d fo
r 24
wee
ksH
isto
ric
cont
rols
, n =
20
Des
crib
e re
vers
al
of c
hole
stas
is
(con
juga
ted
bili
rubi
n