Abstract
OBJECTIVES
An adverse consequence of primarily soybean oil–based parenteral nutrition is the development of intestinal failure–associated liver disease (IFALD), defined as bilirubin ≥ 2 mg/dL. Fish oil–containing lipid emulsion products, such as soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion (SMOF-ILE), have been shown to be beneficial in patients at risk of developing IFALD. This study aimed to review the safety profile of SMOF-ILE and soybean oil–based lipid injectable emulsion (SO-ILE) in regard to liver function and cholestasis in the pediatric and neonatal population.
METHODS
A retrospective review was performed for patients who received SO-ILE or SMOF-ILE over a 3-year period. Patients < 18 years of age who received at least 2 weeks of either product were included. The primary endpoints were 2 consecutive bilirubin readings ≥ 2 mg/dL that were separated by at least 1 week and time to first bilirubin ≥ 2 mg/dL. Secondary endpoints included assessment of select laboratory values (i.e., aspartate aminotransferase, alanine aminotransferase, triglycerides, serum creatinine, serum sodium, coagulation laboratory test, albumin) up to 6 months while on intravenous lipid products. Ursodiol use and mortality were also noted.
RESULTS
There was a higher prevalence of IFALD in pediatric patients receiving SO-ILE than those who received SMOF-ILE (32% vs 12%, p = 0.03). There was no detectable difference in the time it took for IFALD to develop (19 days vs 15 days, p = 0.08).
CONCLUSION
In our cohort of pediatric and neonatal patients, the incidence of IFALD was higher with SO-ILE than with SMOF-ILE.
Keywords: adverse effect, cholestasis, intestinal failure–associated liver disease, lipid emulsion, lipids, parenteral nutrition, pediatrics
Introduction
Parenteral nutrition (PN) is a life-saving option for children and neonates who cannot tolerate enteral nutrition. Patients with intestinal failure, short gut syndrome, and chronic gastrointestinal dysmotility disorders are often in need of PN for extended periods of time. Therefore, PN containing adequate carbohydrates, lipids, and protein is needed to ensure that nutritional needs are met. Lipid injectable emulsions (ILEs) have historically consisted primarily of soybean oil, being rich in phytosterols. When soybean-based ILEs are consumed parenterally instead of enterally, patients experience decreased bile flow and increased bilirubin and serum bile acids. This increases the risk of developing intestinal failure–associated liver disease (IFALD), which has been defined as bilirubin > 2 mg/dL after ≥14 days of PN.1
The proposed mechanism of soybean-associated IFALD is an increase in proinflammatory eicosanoids regulated by the Δ-5-desaturase enzyme system.1 The American Society for Parenteral and Enteral Nutrition states that a reduction in the dose of soybean lipid emulsions to ≤1 g/kg/day reduces the severity and incidence of IFALD. The quality of evidence supporting dose reduction is low; however, decreasing soybean oil content oftentimes results in essential fatty acid deficiency (EFAD).2 Fish oil has been described as being able to increase anti-inflammatory eicosanoids through the Δ-5-desaturase enzyme system, which preferentially metabolizes fish oil over soybean oil. Fish oil has been shown to be beneficial in patients at risk of developing IFALD by being less likely to elevate triglycerides and inflammation,3 while preventing EFAD.4 Therefore, ILE with greater quantities of fish oil have been suggested to be a viable option to prevent IFALD from occurring.
Two of the available and more commonly used ILEs are soybean oil–based ILE (SO-ILE), also known as Intralipid (soybean oil–based lipid injectable emulsion; Fresenius Kabi, Uppsala, Sweden) and soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion (SMOF-ILE), also known as Smoflipid (soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; Fresenius Kabi, Uppsala, Sweden). Each 100 mL of SO-ILE contains approximately 20 g of soybean oil, 1.2 g of egg yolk phospholipids, 2.25 g of glycerin, and water.5 The lipid content of SMOF-ILE is 0.20 g/mL and comprises a mixture of soybean oil, medium-chain triglycerides, olive oil, and fish oil. Each 100 mL of Smoflipid contains approximately 6 g soybean oil, 6 g medium-chain triglycerides, 5 g olive oil, 3 g fish oil, 1.2 g egg phospholipids, 2.5 g glycerin, 16.3 to 22.5 mg all-rac-α-tocopherol, 0.3 g sodium oleate, water for injection, and sodium hydroxide for pH adjustment. Smoflipid was approved by the FDA in July 2016 for PN use in adults as a source of calories and essential fatty acids for PN when oral or enteral nutrition is not possible, insufficient, or contraindicated.6 In 2014, the American Society for Parenteral and Enteral Nutrition released clinical guidelines regarding support for pediatric patients with intestinal failure, PN dependence, and gastrointestinal dysmotility who are at risk of IFALD. However, no recommendations were made concerning SMOF-ILE owing to its lack of FDA approval and availability of studies.2 In March 2017, SMOF-ILE was approved for use at the NewYork-Presbyterian Morgan Stanley Children's Hospital of New York for pediatric patients with intestinal failure, total parenteral nutrition dependence, or those with prolonged NICU stays. Dosing standard of practice for SMOF-ILE and SO-ILE is included in Table 1 and was determined at the discretion of medical/nutrition team. The goal of lipid therapy was to attain adequate nutrition goals while maintaining triglyceride levels that are <200 to 400 mg/dL. Prior to the introduction of SMOF-ILE, the dose of lipids was decreased by 50% if triglycerides were elevated or if IFALD occurred. After SMOF-ILE was added to the formulary and the criteria for use were developed, patients were given SMOF-ILE if they met criteria or if dose reduction of SO-ILE was unsuccessful. The evidence supporting the use of SMOF-ILE in pediatrics is limited and the safety of SMOF-ILE in pediatrics has not yet been established. This study aims to retrospectively compare the effects of SMOF-ILE and SO-ILE on liver function to further elucidate the safety of the 2 ILEs.
Table 1.
SO-ILE and SMOF-ILE Dosing Standard of Practice
| Initiation, g/kg/day | Advance By, g/kg/day | Goal Dose, g/kg/day | |
|---|---|---|---|
| SO-ILE | |||
| Preterm infants | 0.5–1 | 0.5–1 | 3 |
| Term infants | 1 | 1 | 3 |
| Children (1–10 yr) | 1 | 1 | 3 |
| Adolescents | 1 | 1 | 2 |
| SMOF-ILE | |||
| Preterm infants | 0.5–1 | 0.5–1 | 3 |
| Term infants | 0.5–1 | 0.5–1 | 2.5–3 |
| Children (1–10 yr) | 1–2 | 0.5–1 | 2–2.5 |
| Adolescents | 1 | 1 | 2 |
SMOF-ILE, soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; SO-ILE, soybean oil–based lipid injectable emulsion
Materials and Methods
This study is a retrospective, single-center, observational study that was approved by the Columbia University Irving Medical Center Institutional Review Board. Subjects for inclusion were identified from the electronic medical record as patients who received SO-ILE or SMOF-ILE from November 2015 to September 2018. Patients in the SO-ILE group were identified during the period consisting of the 15 months before SMO-FILE was added to formulary. Patients in the SMOF-ILE group were identified during the period consisting of the 15 months after SMOF-ILE was added to formulary. Pediatric patients (≤18 years of age) who were unable to meet total enteral nutrition needs and required at least 14 consecutive days of either SMOF-ILE or SO-ILE as a component of PN were included in the study. Exclusion criteria included patients who developed cholestasis for causes unrelated to PN and patients who received SO-ILE for 14 days or more before they were transitioned to SMOF-ILE. Furthermore, patients in the SO-ILE group were excluded if they would not have met the institution's criteria for use of SMOF-ILE if it was available during that period. The SMOF-ILE criteria for use included 1) PN > 14 days; 2) presence of fatty acid deficiency on other ILEs; 3) intestinal failure; or 4) any transplant. Patients were included in the SMOF-ILE group if they had received only SMOF-ILE, or if they been transitioned to the SMOF-ILE and had received the SO-ILE for <14 days prior to transitioning.
The primary endpoints included the incidence of IFALD defined as 2 consecutive bilirubin readings ≥ 2 mg/dL separated by at least 1 week and the time to the first bilirubin reading ≥ 2 mg/dL. Secondary endpoints were mortality, ursodiol usage, and bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides, creatinine, sodium, international normalized ratio (INR), and albumin trends up to 6 months while on ILEs.
For statistical analysis, categorical variables were analyzed by using χ2 test or Fisher exact test, and continuous variables were analyzed by using Student t test. p values < 0.05 were considered statistically significant. Data were analyzed by using Statistical Package for the Social Sciences (SPSS, ICM, Armonk, NY).
Results
Figure 1 depicts how patients were identified for inclusion in this study. Five hundred forty-eight patients were screened for study inclusion, and 101 patients were included in this study, with 60 patients in the SMOF-ILE group and 41 patients in the SO-ILE group. Table 2 summarizes the baseline characteristics of the patients included in the study. The patients in the SMOF-ILE group weighed more than the patients in the SO-ILE group (5th vs 25th weight percentile, p = 0.02). The median age at admission of the patients within the SMOF-ILE group was higher than that of the patients in the SO-ILE group, though not statistically significant (300 vs 31 days, p = 0.93). About half (51%) of the patients were white and most patients were males. The most common reasons patients were admitted to the hospital were gastrointestinal disease and premature birth. There was no difference between the median length of therapy between the 2 groups (32 days vs 28.5 days, p = 0.12) (Table 2). There were more patients in the SMOF-ILE group who received PN and an ILE for malnutrition (15% vs 47%, p = 0.01) and there were more patients in the SO-ILE group who received PN and an ILE for altered gastrointestinal function (44% vs 27%, p = 0.01) (Table 3).
Figure 1.
Inclusion of patients.
Table 2.
Baseline Characteristics
| Demographic | SO-ILE (n = 41) | SMOF-ILE (n = 60) | p value |
|---|---|---|---|
| Age, median (IQR), days | 31 (0, 795) | 300 (0, 1095) | 0.93 |
| Sex, n (%), male | 26 (63) | 31 (52) | 0.33 |
| Gestational age, median (IQR), wk | 36 (31, 37) | 31 (25, 38) | 0.17 |
| Weight, median (IQR), percentile | 5 (2, 50) | 25 (2.75, 50) | 0.02 |
| Height, median (IQR), percentile | 2 (2, 50) | 10 (2, 50) | 0.28 |
| BSA, median (IQR), m2 | 0.31 (0.22, 0.51) | 0.47 (0.26, 0.69) | 0.53 |
| Race, n (%) | |||
| White | 21 (51) | 27 (45) | 0.28 |
| Black | 10 (24) | 21 (35) | 0.83 |
| Hispanic | 7 (17) | 1 (2) | 0.01 |
| Asian | 3 (7) | 2 (3) | 0.39 |
| Other* | 0 (0) | 8 (13) | 0.02 |
| Home parenteral nutrition, n (%) | 2 (5) | 6 (10) | 0.47 |
| Transplant, n (%) | 11 (27) | 16 (25) | 0.83 |
| Length of stay, median (IQR), days | 65 (36, 130) | 70 (40, 127.5) | 0.53 |
| Length of therapy, median (IQR), days | 32 (23, 55) | 28.5 (20.75, 44) | 0.12 |
| Hepatotoxin use,† n (%) | 17 (41) | 23 (38) | 0.91 |
| Propofol use, n (%) | 1 (2) | 4 (7) | 0.65 |
| Primary diagnosis, n (%) | |||
| Prematurity‡ | 11 (27) | 17 (28) | 0.95 |
| Cancer | 2 (5) | 10 (17) | 0.11 |
| Cardiomyopathy | 5 (12) | 7 (12) | 0.81 |
| GI disease | 12 (29) | 17 (28) | 0.90 |
| Genetic disorder | 2 (5) | 2 (3) | 0.90 |
| Infection | 3 (7) | 5 (8) | 0.85 |
| Respiratory disease | 4 (10) | 4 (6) | 0.84 |
BSA, body surface area; SMOF-ILE, soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; SO-ILE, soybean oil–based lipid injectable emulsion
* Indian, Pakistani, or unknown races.
† Hepatotoxin use was defined as the receipt of a hepatotoxic medication (i.e., fluconazole, micafungin, linezolid) while on ILE and up to 6 mo.
‡ Prematurity was defined as patients born at <37 wk.
Table 3.
Parenteral Nutrition With ILE Indications
| Indications, n (%) | SO-ILE (n = 41) | SMOF-ILE (n = 60) | p value |
|---|---|---|---|
| Malnutrition | 8 (15) | 28 (47) | 0.01 |
| Altered GI function* | 23 (44) | 16 (27) | 0.01 |
| Prematurity | 12 (23) | 11 (18) | 0.30 |
| Congenital heart disease | 3 (6) | 0 (0) | 0.06 |
| Cancer | 4 (8) | 3 (5) | 0.44 |
| Other medical condition† | 2 (4) | 1 (2) | 0.56 |
ILE, lipid injectable emulsion; SMOF-ILE- soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; SO-ILE, soybean oil–based lipid injectable emulsion
* Altered GI function included short-bowel syndrome, GI fistulas, intestinal obstruction, pancreatitis, gastroschisis, meconium ileus, and Hirschsprung disease.
† Other medical conditions included respiratory distress, surgery, and multisystem organ failure.
Table 4 summarizes the primary endpoints and a selection of the secondary endpoints for this study. For the primary endpoints of incidence of IFALD and time to develop IFALD, more patients in the SO-ILE group developed IFALD (32% vs 12%, p = 0.03). These patients took slightly longer to develop IFALD (19 days vs 15 days, p = 0.08), though this difference was not statistically significant. There was no difference between the study groups in regard to ursodiol use and mortality (Table 4).
Table 4.
Primary and Secondary Endpoints
| Endpoints | SO-ILE (n = 41) | SMOF-ILE (n = 60) | p value |
|---|---|---|---|
| IFALD, n (%) | 13 (32) | 7 (12) | 0.03 |
| Days to IFALD, median (IQR) | 19 (14, 35) | 15 (13, 20) | 0.08 |
| Ursodiol use,* n (%) | 12 (29) | 13 (22) | 0.53 |
| Mortality, n (%) | 10 (24) | 9 (15) | 0.35 |
IFALD, intestinal failure–associated liver disease; ILE, lipid injectable emulsion; SMOF-ILE, soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; SO-ILE, soybean oil–based lipid injectable emulsion
* Ursodiol use was defined as the receipt of an ursodiol dose within 6 months after the start of ILE.
Among patients without IFALD, AST trends over 6 months were similar between the SMOF-ILE and SO-ILE groups (37 ± 4 vs 36.6 ± 3, p = 0.86). There was a similar trend in ALT over 6 months (25 ± 4 vs 23.9 ± 5, p = 0.71; Figure 2). However, among patients with IFALD, the SO-ILE group had higher AST at 3 to 6 months (65 ± 3 vs 38 ± 1, p = 0.06), but differences in ALT were not significantly different (49.5 ± 6 vs 31 ± 1, p = 0.06) at 3 to 6 months (Figure 2). Bilirubin trends were similar between the 2 groups in patients who did not have IFALD. However, bilirubin was higher in the SO-ILE group in patients with IFALD (2.1 ± 0.9 vs 0.9 ± 0.4, p = 0.03). Levels were >2 mg/dL for up to 1 month for the patients in the SO-ILE group with IFALD and were never >2 mg/dL for patients in the SMOF-ILE with IFALD (Figure 2). Serum creatinine levels were higher in the SO-ILE group initially, regardless of the occurrence of IFALD. Otherwise, the serum creatinine trends were similar between the 2 groups. Sodium, triglycerides, INR, and albumin trends were similar between the 2 treatment groups (Table 5). Patients with IFALD had higher triglyceride levels than patients with no IFALD (Intralipid 129 ± 32 vs 79.2 ± 10.5, p = 0.01; Smoflipid 129 ± 32 vs 98.5 ± 4, p = 0.0003), but triglyceride levels were never >200 mg/dL in either group (Table 5).
Figure 2.
AST, ALT, and Bilirubin Trends Over 6 Months in Patients with and Without IFALD.
Table 5.
Median Values for Additional Laboratory Study Trends in Patients With and Without IFALD Over 6 mo
| Laboratory Test | Baseline | 2 wk | 1 mo | 3 mo | 6 mo | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| IFALD | No IFALD | IFALD | No IFALD | IFALD | No IFALD | IFALD | No IFALD | IFALD | No IFALD | |
| Albumin, g/dL | ||||||||||
| SO-ILE | 3.1 | 3.4 | 3.0 | 3.5 | 2.9 | 3.55 | 3.2 | 3.9 | 3.6 | 3.85 |
| SMOF-ILE | 2.9 | 3.0 | 3.1 | 3.25 | 3.2 | 3.3 | 3.8 | 3.7 | 3.9 | 3.9 |
| INR | ||||||||||
| SO-ILE | 1.2 | 1.1 | 1.1 | 1.1 | 1.1 | 1.1 | 1.1 | 1.1 | 1.1 | 1.2 |
| SMOF-ILE | 1.2 | 1.2 | 1.2 | 1.2 | 1.4 | 1.1 | 1.2 | 1.2 | 1.2 | 1.1 |
| Serum creatinine, mg/dL | ||||||||||
| SO-ILE | 0.63 | 0.52 | 0.36 | 0.31 | 0.3 | 0.28 | 0.33 | 0.27 | 0.31 | 0.27 |
| SMOF-ILE | 0.36 | 0.34 | 0.28 | 0.28 | 0.24 | 0.28 | 0.29 | 0.31 | 0.24 | 0.31 |
| Serum sodium, mEq/L | ||||||||||
| SO-ILE | 139 | 137 | 139 | 139 | 138 | 139 | 139 | 138 | 139 | 138 |
| SMOF-ILE | 139 | 139 | 139 | 139 | 138 | 137 | 139 | 139 | 140 | 139 |
| Triglycerides, mg/dL | ||||||||||
| SO-ILE | 71 | 104 | 72 | 153 | 78 | 173 | 78 | 103 | 97 | 112 |
| SMOF-ILE | 106 | 153 | 102 | 177 | 96 | 137 | 96 | 137 | 96 | 137 |
IFALD, intestinal failure–associated liver disease; INR, international normalized ratio; SMOF-ILE, soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion; SO-ILE, soybean oil–based lipid injectable emulsion
Discussion
This study showed that there was a 20% higher incidence of IFALD for patients receiving SO-ILE than for patients who received SMOF-ILE. It is also worthwhile to note that patients in the SO-ILE group appeared to be younger with a higher risk of developing IFALD, which could have influenced the high rates of IFALD in the SO-ILE group. However, this difference was not confirmed to be statistically significant.
It is worthwhile to note that AST and ALT trends were similar in patients without IFALD. However, in patients with IFALD, the SO-ILE had higher AST and ALT levels at 3 to 6 months, suggesting that this ILE may contribute to liver dysfunction. Serum creatinine levels were initially higher in the SO-ILE group. This could be explained by the younger age of these patients, even though it was confirmed that the age difference between the study groups was not statistically significant. Bilirubin trends were higher in the SO-ILE group for up to 1 month in patients with IFALD. This could be explained by the younger age of these patients. However, statistical analysis of these data points has not been performed so further research is needed to confirm these conclusions.
This study adds to the literature by examining the use of SMOF-ILE in pediatric patients at risk of developing IFALD and receiving ILE. Three randomized controlled studies were published in 2010, comparing SMOF-ILE and SO-ILE for safety, efficacy, and tolerability. Tom-sits et al7 conducted a study including 60 premature neonates randomly assigned to receive SO-ILE or SMOF-ILE. These authors concluded that there was no difference in serious adverse events, lipid profile, growth parameters, and total bilirubin.7 Goulet et al8 arrived at a similar conclusion in a study that included 28 PN-dependent patients aged 5 months to 11 years. In addition, SMOF-ILE was shown to decrease total bilirubin. The opposite was true for SO-ILE.8 Skouroliakou et al9 conducted a study including 32 premature infants to evaluate the effect of SMOF-ILE on antioxidant status. Total antioxidant potential increased in the SMOF-ILE group, but the same effect was not observed with the SO-ILE group. In 2012, a randomized controlled trial including 53 premature neonates who received an ILE product over 7 days showed that there was no difference in triglyceride, growth parameters, or serious adverse events between SMOF-ILE and SO-ILE. However, SMOF-ILE produced a greater reduction in total and conjugated bilirubin from baseline. Unfortunately, this 2012 study was limited by the short duration of <3 weeks of PN, limiting the study's applicability to patients who require longer periods of PN.10
More studies have been published exploring the incidence of IFALD between these 2 products. A meta-analysis on ILEs and the risk of hepatotoxicity in infants and children examined 23 randomized controlled trials and showed there was no difference in the rate of cholestasis or bilirubin levels with short-term use between different ILEs. However, when use of PN and ILE is expected to be longer than 2 weeks, the use of SMOF-ILE may be beneficial. Unfortunately, the data were limited to definitively make this conclusion.11 Later, a randomized controlled trial was published looking at ILE use in low birth weight infants. Contradictory to our study, the authors showed that IFALD was not significantly reduced with the use of SMOF-ILE.12 However, Classon et al13 later published a study that found that patients on SO-ILE experienced significantly more cholestasis. There was no difference in peak bilirubin levels but patients on SMOF-ILE normalized more quickly. Unfortunately, this study only included a small number of infants. Therefore, our study adds to the literature by concluding that SMOF-ILE decreases the incidence of IFALD in a larger number and wider variety of patients than previous studies, including premature neonates and older children who are at risk for developing IFALD, particularly those who are on PN for >2 weeks.
One of the limitations of the current study was the sample size, which limits this study's ability to detect differences between the 2 ILE groups. This study was also limited by a lack of evaluation of the impact of sepsis, surgery, or blood transfusion, which may play important roles in the pathogenesis of IFALD. Various strategies are used in practice to minimize the incidence of IFALD and development of EFAD, which include reductions in lipid dosing, cycling of PN solutions, or the increase of enteral nutrition in adjunct with PN use. Given the heterogeneity of the patient population, this study did not assess the above practices and should be recognized as a potential limitation when interpreting the results. The dose of the SMOF-ILE is not equivalent to that of the SO-ILE. In fact, 3 g/kg/day of SMOF-ILE is needed to provide similar essential fatty acids as 1 g/kg/day of SO-ILE. Therefore, from this study, we cannot conclude that SMOF-ILE is a better choice of ILE. However, the results of this study do suggest that these patients are at risk for developing IFALD, with 1 of every 3 patients experiencing IFALD while on SO-ILE versus 1 of every 8 patients on SMOF-ILE.
Conclusion
When used as the ILE portion of PN, the incidence of IFALD is decreased with the use of SMOF-ILE when compared with SO-ILE. However, further research and multicenter collaboration would be beneficial to validate this conclusion.
Acknowledgments
Preliminary results were presented at Eastern States Regional Meeting on April 28, 2019; and Pediatric Pharmacist Association Annual Meeting Resident Project Presentations in Oklahoma City, OK, on April 13, 2019.
ABBREVIATIONS
- ALT
alanine aminotransferase
- AST
aspartate aminotransferase
- EFAD
essential fatty acid deficiency
- FDA
US Food and Drug Administration
- GI
gastrointestinal
- IFALD
intestinal failure–associated liver disease
- ILEs
lipid injectable emulsions
- INR
international normalized ratio
- NICU
neonatal intensive care unit
- PN
parenteral nutrition
- SMOF-ILE
soybean oil, medium-chain triglycerides, olive oil, fish oil lipid injectable emulsion
- SO-ILE
soybean oil–based lipid injectable emulsion
Footnotes
Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. All authors have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Ethical Approval and Informed Consent. Given the nature of this study, the institution review board/ethics committee did not require review of the project nor did they require informed consent.
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