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Invited Review

Composite Lipid Emulsion for the Infant at Risk of Intestinal Failure–associated Liver Disease: The Canadian Perspective

Silverman, Jason A.∗,†; Turner, Justine M.∗,†; Wales, Paul W.‡,§

Author Information
Journal of Pediatric Gastroenterology and Nutrition: September 2020 - Volume 71 - Issue 3 - p 283-287
doi: 10.1097/MPG.0000000000002794

Abstract

Across the lifespan, it is without question that neonates, particularly those born preterm, are at greatest risk of intestinal failure–associated liver disease (IFALD) due to the requirement for parenteral nutrition (PN) (1). Cholestasis is reported to develop in 43% of infants requiring PN for 29 to 56 days and 72% of those requiring PN for longer than 56 days (1). Earlier gestation, longer duration of PN, and underlying surgical diagnoses, such as necrotizing enterocolitis, are all predictive of increased risk (1). Traditionally, when IFALD progressed to severe end-stage liver disease, death, or transplantation occurred in 38% (2).

Recently it has been recognized that traditional plant-based parenteral lipids play a key role in the development of IFALD (3). In particular, replacing plant-based lipids with pure fish oil lipid emulsion (FOLE) (Omegaven, Fresenius Kabi, Bad Homburg, Germany) has emerged as a treatment that can reverse IFALD, increase survival, and avoid the need for transplantation (4). Whether the benefit comes directly from the addition of fish oil or more specifically from the reduction of the plant-based lipid dose remains contentious. Strategies that significantly restrict plant based lipids can also reverse IFALD (5) and it has been difficult to prove one strategy superior to the other (6). The survival of infants with intestinal failure has dramatically improved to >90% in the current era (7). Although the development of experienced multidisciplinary care provider teams has been a major contributing factor, it is clear that new approaches to parenteral lipid therapy have also contributed (7,8).

SMOFlipid (Fresenius Kabi) is a composite lipid emulsion (CLE) that contains 4 oils: soy, medium-chain triglycerides (MCTs), olive oil, and fish oil. Although other CLEs exist, in the present article CLE will refer only to this product. CLE simultaneously achieves plant-based lipid dose restriction (being 30% soy oil, compared to Intralipid; Fresenius Kabi), a 100% soy oil lipid emulsion (SOLE), and provides some fish oil lipid (15%). For context, at a dose of 2 g · kg−1 · day−1 CLE will deliver the equivalent soy oil dose of Intralipid dosed at 0.6 g · kg−1 · day−1g/kg/d and the equivalent fish oil dose as FOLE dosed at 0.3 g · kg−1 · day−1. It was developed for critically ill adults, with a view to reducing systemic inflammation, but has been widely studied for its safety and potential efficacy in neonates, given the advantage of added long chain polyunsaturated fatty acids (LC-PUFAs) (9–14). To date, there have been few published studies and specifically few randomized controlled trials of its use for IFALD prevention and IFALD reversal (15–19).

CLE has been licensed in Europe for pediatric use since 2009. In Canada, it was approved for use in adults by Heath Canada in 2013. It is used in many Canadian pediatric institutions on an off-label basis. The FDA approved CLE for adults in 2016. Therefore, on a global basis the greatest long-term experience with this lipid is European. It was not widely used as the first choice of lipid 10 years ago (20,21). At that time in the United Kingdom for pediatric patients Intralipid still predominated, whereas the most common second-line lipid for IFALD was CLE, followed by FOLE (20). The predominant lipid for neonates in France was a combination of soy oil and MCTs (21). More recent data, presented at the Congress of Intestinal Rehabilitation and Transplantation (2019) suggests the trend has moved toward CLE as first-line choice for pediatric patients on home PN across France (22). Currently, in Canada CLE accounts for approximately 70% of total parenteral lipid use and 80% of pediatric lipid use, even though it fails to have a specific pediatric indication (Anon. Personal communication. Fresenius Kabi.).

Authors’ Clinical Experience Using Composite Lipid Emulsion for Infants at Risk of Intestinal Failure–Associated Liver Disease

Both our institutions (Stollery Children's Hospital, Edmonton and SickKids, Toronto, Canada) use CLE in a similar manner for all neonates receiving PN therapy. SOLE may still be used for PN expected to be of short duration (typically <2 weeks), and in older children requiring PN for indications other than intestinal failure. When used, CLE is delivered at initiation of PN treatment at conventional doses of 2 to 3 mg · kg−1 · day−1 to meet nutritional targets. PN components are weaned proportionally as enteral feeds are advanced. The Group for Improvement of Intestinal Function and Treatment (GIFT, Toronto, Canada) has used CLE as the default lipid emulsion for all patients with intestinal failure since 2013 and has used Omegaven once since that time for hepatic salvage. The Children's Intestinal Rehabilitation Program (CHIRP, Edmonton, Canada) has used CLE for intestinal failure patients, also since 2013, and has also only used FOLE once since that time. Both institutions have seen a dramatic decrease in cholestasis, improved survival, and reduction in transplantation (23).

At the Stollery Hospital, since 2013, there has not been isolated liver transplantation or listing for IFALD where onset was during that era. There have been 3 multivisceral transplants (MVTs) for IFALD with onset before 2013. Since 2013, At SickKids, there has not been isolated liver transplantation or MVT for IFALD of onset during that era. One patient with intestinal failure onset after 2013 was listed for MVT at SickKids; however, this patient also had an isolated biliary stricture.

What Is the Evidence for Composite Lipid Emulsion in Prevention and Treatment of Pediatric Intestinal Failure–associated Liver Disease?

IFALD represents as cholestasis that may be progressive associated with fibrosis and possible eventual hepatic failure. Risks for IFALD are numerous, but include prolonged provision of PN, specific components of PN, inadequate enteral intake, prematurity, shorter bowel lengths, and episodes of sepsis (24). CLE may potentially address several purported mechanisms by which soy oil–based lipid emulsions contribute to the pathogenesis of IFALD. These include the shift toward a predominance of proinflammatory cytokines produced through the metabolism of omega-6 fatty acids, the potentially deleterious effects of exposure to soy phytosterols, as well as a relatively low content of α-tocopherol increasing free radical exposure (25–28). Compared to plant-based lipid emulsions that contain primarily omega-6 fatty acids, which are metabolized to produce proinflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, fish oil–containing emulsions provide more omega-3 fatty acids, which are metabolized into anti-inflammatory eicosanoids, such as prostaglandin E3, leukotriene B5, and thromboxane A3(26,27). In addition, as soy phytosterols have been implicated in the pathogenesis of liver injury, CLE may provide benefit simply through reduced exposure, being composed of only 30% soy oil. Lastly, CLE contains greater concentrations of α-tocopherol compared to SOLE (200 vs 38 mg/L) (29), which may provide benefit in scavenging free radicals that may contribute to hepatotoxicity (30). While FOLE offers high omega-3 content, avoid soy phytosterols and provide higher α-tocopherol content, the provision of 100% fish oil–based lipid emulsions has raised concerns about the development of essential fatty acid deficiency (EFAD) (31). This is both because of the lower content of the essential fatty acids (linoleic acid and alpha-linolenic acid) and the high content of omega-3 fatty acids that can interfere with the metabolism and tissue accretion of arachidonic acid (ARA) (32). At standard doses, CLE avoids these concerns through adequate provision linoleic acid and alpha-linolenic acid and through a more moderate balance of omega-3:omega-6 fatty acids (Table 1).

T1
TABLE 1:
Composition of commonly used parenteral lipids for infants with intestinal failure

There has been significant interest in the potential for CLE to both reverse and prevent IFALD, but unfortunately published data on the use of CLE in infants are limited. Most studies have been retrospective, comparing noncontemporaneous time periods, and therefore may be confounded by potential differences in medical or surgical care. Although small prospective studies have been published, follow-up periods have been short. Systematic reviews have also been published, but not surprisingly they are limited by heterogeneity and low-quality evidence. Here we outline currently available data on the use of CLE in both premature infants and older infants to treat or prevent IFALD.

Reversal of IFALD was first documented in 2012, in a series of 8 infants with IFALD who were transitioned to CLE compared to historical controls (16). Despite the patients remaining on significant volumes of PN for more than 6 months, and having a higher starting bilirubin level, 5 of 8 patients who received CLE completely resolved their cholestasis, compared to only 2 of 9 historical controls (16). A more recent prospective, randomized, double-blinded multicenter Canadian study in infants with intestinal failure, demonstrated the potential for CLE, provided at conventional doses, to prevent the progression of early IFALD (defined as a conjugated bilirubin of 17–50 or 1–3 mg/dL) compared to a contemporaneous control group receiving Intralipid (17). At the end of the study period, infants receiving CLE had significantly lower conjugated bilirubin compared to controls (mean difference, −59 μmol/L) (17). In addition, there was a significant difference in the number of infants who continued to have a conjugated bilirubin >50 μmol/L (2/11 in the CLE group compared to 9/13 in the Intralipid group) (17). Despite improvement in cholestasis, and no significant difference in transaminases between groups, the gamma-glutamyl transferase in the CLE treated group was significantly higher at study completion. In contrast, another study, looking at pediatric patients with intestinal failure aged 0 to 16 years (median age of 0.6 years) found all liver chemistries improved significantly on both CLE and another MCT-containing lipid emulsion (Lipofundin, B. Braun, Melsungen, Germany); however, improvement in gamma-glutamyl transferase was significantly greater in the CLE group (29).

Despite evidence to suggest that CLE can reverse IFALD at conventional dosing, a published series reported 2 infants who developed IFALD while receiving CLE, which subsequently resolved following a switch to FOLE at 1 g · kg−1 · day−1 as rescue therapy (33). Although previous studies have documented reversal of IFALD using FOLE (4), this was the first report of such therapy for infants previously receiving CLE. This report is in keeping with practice within our own centers where, rarely, infants who develop severe IFALD (generally conjugated bilirubin >100 μmol/L) despite the use of CLE are eligible to receive rescue therapy with FOLE, presuming sepsis or other causes for cholestasis have been excluded (33). Of note, this has occurred only once each in our centers in the last 5 years.

Lipid minimization strategies have also been shown to reverse IFALD (5). There are, however, considerable concerns regarding adequate weight gain, compromise to neurodevelopment and EFAD. In a published case, an infant with IFALD who failed to respond to lipid minimization with Intralipid (1 g · kg−1 · day−1) had progression of IFALD and biochemical evidence of EFAD when switched to CLE at the same dose. After increasing the dose of CLE to a more conventional 2 g · kg−1 · day−1, the infant had reversal of both IFALD and EFAD (34). This emphasizes the importance of providing CLE at conventional dosing for most infants to ensure adequate nutrition, while also receiving hepatoprotective benefits.

A recent systematic review and meta-analysis examined studies on the prevention of, and reversal of, PN-associated cholestasis in neonates receiving fish oil−containing lipid emulsions (35). A total of 7 studies met inclusion criteria, with 3 studies on reversal of PN-associated cholestasis and 4 studies on prevention (35). All fish oil−containing lipid emulsions (including CLE) were associated with greater, and faster resolution of cholestasis compared to controls (35). Although there was a trend toward decreased incidence of cholestasis in neonates receiving FOLE, this did not reach significance (35). There was no evidence for prevention of cholestasis using CLE (35).

Other studies have confirmed no clear benefit in CLE for prevention of cholestasis in at risk infants, where importantly the most important risk factor for the development of IFALD was total duration of lipid exposure regardless of lipid emulsion provided (13,36). Unfortunately, many studies for IFALD prevention (including with 100% fish oil) (6) may be inadequately powered, given the rates of development of IFALD are in general low, or may not include treatment periods of sufficient length to detect treatment efficacy. A recent study of 388 preterm infants found that very low birth weight neonates provided CLE had significantly lower incidence of IFALD and lower peak conjugated bilirubin levels compared with those in a previous era who received an alternate MCT/soy lipid emulsion (Lipofundin) (37). It is important to note that in this study, the control group received a lipid emulsion that already offers potential benefits over soy oil based lipids, similarly reducing total exposure to phytosterols and omega-6 long chain fatty acids. Overall, limited evidence suggests that CLE may provide some protection against the development of IFALD in preterm neonates, but clearly further studies are required (23).

Outside of the neonatal period, several studies have examined the potential impact of CLE on the risk of developing cholestasis while on PN. A recent retrospective study compared groups of infants with IF who received either SOLE or CLE with a minimum of 12 months of follow-up (23). There were no differences between groups in terms of diagnosis, bowel length, or percentage of PN provided at each of the examined time points. Infants on CLE had significantly lower conjugated bilirubin levels at 3 months, and were less likely to reach higher conjugated bilirubin levels and had improved weight z scores over the first 6 months when compared to infants on SOLE (23). Another retrospective comparison between pediatric oncology patients receiving either CLE or soy-based lipid emulsion over 2 weeks showed no cholestasis in the study group (38). No difference in cholestasis (conjugated bilirubin ≥1 mg/dL or 17.1 μmol/L) was noted in surgical infants who received either CLE or Lipofundin for at least 2 weeks, although goal recruitment was not attained (39). Rates of increase in conjugated bilirubin level were shown to be significantly lower in a mixed cohort of hospitalized pediatric patients receiving CLE compared to age and diagnosis-matched controls receiving Intralipid, despite similar median lipid dose (18). Lastly, a larger prospective, randomized study examined markers of hepatotoxicity in 160 infants undergoing surgery who received either CLE or an alternate combination MCT/long-chain triglycerides lipid emulsion for at least 2 weeks. Both parenteral and enteral nutrition ordering was similar in both groups. Markers of hepatotoxicity (alanine aminotransferase, aspartate aminiotransferase, and conjugated bilirubin) were all significantly lower in the CLE group compared to MCT/long-chain triglycerides at the end of 4 weeks on PN, although none of these markers were different at the 2-week timepoint (40). This suggests that CLE may be protective against hepatotoxicity of PN, particularly with longer exposures.

Systematic review of the available literature to date, supports that CLE administered at conventional doses can reverse IFALD (16,17,29). Early evidence also appears to suggest that the risk of cholestasis may be reduced in premature infants when receiving CLE. However, as was noted, infants can develop IFALD while receiving CLE, requiring rescue therapy with FOLE (33). At this time there is, however, less clear evidence overall for CLE in the prevention of IFALD. To clarify the role of CLE in IFALD prevention, much needed studies are underway, with 4 trials currently listed on ClinicalTrials.gov that are recruiting or in a prerecruitment phase, including a multicenter US-based trial on hospitalized neonates or infants requiring >28 days of PN with a target enrollment of 400 subjects (41).

Safety Concerns With Composite Lipid Emulsion

There is actually considerable safety data for CLE in neonates, albeit over the short term, as it is most often used in neonates. Three randomized controlled trials included 80 preterm infants (≤34 weeks), weighing from 500 to 2500 g, given CLE 2 to 3.5 g · kg−1 · day−1, and compared to 81 similar infants given soy lipid (9,11,12). Studied for 14 days or less, there was no evidence of serious adverse events and comparable weight gain between groups. Findings in regard to short-term lipid tolerance have been more variable, with either no differences (9,11,12) or a tendency to increase triglycerides with CLE, at least when delivered at higher doses (3.5 g · kg−1 · day−1) (42). In contrast lipid tolerance has, however, been shown to improve over the longer term when comparing to a mixed MCT/soy lipid over a similar dose range (39). Increase in plasma α-tocopherol levels have been demonstrated with both short- and long-term CLE treatment, consistent with the higher content; however, the clinical significance of this finding remains unknown (9,15). Allergy to parenteral lipids is possible, in particular allergy to soy and fish oils as reported, with the product monograph for CLE also carrying a warning for those with severe egg allergy.

There is emerging safety data for longer term use of CLE. Goulet et al, studied 15 infants and older pediatric patients on home PN with CLE, compared to 13 on home PN with soy lipid, over a 4-week period at doses approximating 2 g · kg−1 · day−1. There were essentially no differences in growth, adverse events, lipid tolerance, or peroxidation. There was an increase in α-tocopherol and decrease in bilirubin in the CLE-treated children. Diamond et al (17) provided CLE or SOLE to infants for up to 12 weeks with a further 4-week follow-up period. No difference in adverse events was noted between study groups, and specifically there were no adverse events in the CLE group attributable to lipid (17). More recently, Jiang et al (40), studied 74 surgical neonates treated with CLE for more than 2 weeks and 22 for more than 4 weeks, compared to 86 and 24 neonates respectively given standard MCT/soy lipid therapy. No differences in rates of sepsis, biomarkers of inflammation, or weight gain were noted. At the end of 4 weeks the conjugated bilirubin was, however, lower in the CLE treated group (40). Lastly, a recent observational study that followed infants using CLE for a period of 1 year reported no adverse events related to CLE administration (23).

A safety concern that has been raised with the use of CLE in infants at risk of IFALD is the reported development of EFAD (43). Linoleic acid and alpha-linolenic acid are 2 omega-6 PUFAs that are considered essential as they cannot be synthesized from other fatty acids. PUFAs are involved in a number of crucial physiologic processes including being incorporated into cell membranes, and they are metabolized into inflammatory and anti-inflammatory mediators (44). Clinical signs of EFAD may include impaired growth, poor wound healing, hair loss, and rash (44). Infants with intestinal failure are at risk for EFAD due to inadequate absorption in the absence of an adequate parenteral supply of essential fatty acids. This has most convincingly been reported, at least based on biochemical evidence (triene:tetraene ratio >0.2), when the lipid dose was restricted <1 g · kg−1 · day−1, which would represent a dose restriction of Intralipid to 0.3 g · kg−1 · day−1(5). In one case, an infant with IFALD who failed to respond to lipid minimization with SOLE (1 g · kg−1 · day−1) developed biochemical evidence of EFAD when switched to CLE at the same dose. After increasing the dose of CLE to a more conventional 2 g · kg−1 · day−1, the infant had reversal of both IFALD and EFAD (34).

In Canada and in Europe the clinical practice has been to use CLE at conventional doses and in doing so to not routinely measure for biochemical EFAD. Only recently has data on fatty acid profiles for children treated long term with CLE been presented (45). These data were consistent with the majority of short- and long-term neonatal safety studies that suggest following treatment with CLE plasma and red blood cell membranes become enriched with LC-PUFAs, notably the developmentally important omega-3 LC-PUFA docosahexaenoic acid, without compromising enrichment with ARA (9,12,46,47). In some cases a reduction in ARA has, however, been noted (11,42) and so this issue does require further investigation.

CONCLUSIONS

The long-term outlook for children with intestinal failure in this modern era is excellent and optimal growth and neurodevelopment are critically important goals for nutrition support in this population. CLE is one of the few treatments available for neonates at risk of IFALD that can be delivered at conventional doses. Hence, a potential advantage of CLE is the possibility to support optimal growth in comparison to lipid dose restriction (5). In fact, in the general neonatal population, CLE appears to be superior to traditional lipid at standard doses for neonatal growth (46,48). Considerable global experience, as well as short- and medium-term safety studies, confirms the safety of CLE, used at conventional doses, for children at risk of IFALD, including very preterm infants. In Canada, CLE is currently the lipid emulsion of choice for all infants at risk of IFALD, supported by evidence that this emulsion can reverse IFALD and emerging evidence, beyond our clinical experience, for IFALD prevention.

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Keywords:

cholestasis; composite lipid emulsion; essential fatty acids; long chain fatty acids; parenteral nutrition; preterm

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