2013 incidence, prevention, and treatment of pn-associated cholestasis and if-associated ld in...

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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

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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

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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).



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.




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.



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




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



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




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.



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)


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).



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




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



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).

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