360 jpen j parenter enteral nutr 2014 wales 0148607114527772

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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

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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.


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


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.



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.



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.


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.



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.


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%.


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)


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

360 jpen j parenter enteral nutr 2014 wales 0148607114527772

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