Use of Fish Oil Emulsion in Parenteral Nutrition: A Review of 20 Cases

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1 503986CANXXX / ICAN: Infant, Child, & Adolescent NutritionICAN: Infant, Child, & Adolescent Nutrition research-articlexxxx ICAN: Infant, Child, & Adolescent Nutrition February 2014 Evidence-Based Practice Reports Use of Fish Oil Emulsion in Parenteral Nutrition: A Review of 20 Cases Veronique Groleau, MD, Maxime Thibault, BPharm, MSc, and Valerie Marchand, MD Abstract: Background. Parenteral nutrition provides nutritional support when the gastrointestinal tract is nonfunctional, but it may lead to intestinal failure associated liver disease (IFALD). Substituting the soybean oil based lipid emulsion (SOLE) with fish oil based lipid emulsion (FOLE) has been associated with improvement of IFALD. Materials and methods. Medical records of patients who received parenteral FOLE for 1 month were reviewed for total and direct bilirubin, alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) levels. Results. Twenty patients were included. They were between 0.5 and months at initiation of FOLE. They had been on parenteral nutrition with SOLE for a median of 46 days before the initiation of FOLE. Fifteen patients received a mixture of the 2 lipid emulsions, among them, only the 5 patients who received FOLE for >20 weeks showed an improvement in their bilirubin levels. One patient received SOLE and was then switched to FOLE monotherapy at which point his bilirubin level normalized. Four patients received a mixture of both lipid emulsions followed by FOLE monotherapy. Their bilirubin levels improved only after SOLE was discontinued. Changes in ALT and GGT were not significant. Conclusion. FOLE monotherapy was more effective than a mixture of SOLE and FOLE when treating preexisting IFALD, and the improvement in bilirubin was seen earlier with FOLE monotherapy treatment. Keywords: fish oil emulsion; intestinal failure associated liver disease; children Introduction Parenteral nutrition (PN) is essential to provide adequate nutritional support when the gastrointestinal tract is either nonfunctional or partly functional. Longterm PN often leads to intestinal failure associated liver disease (IFALD) and may progress to irreversible liver damage. The etiology of IFALD is likely multifactorial. 1 The toxicity of manganese 2 and phytosterols, 3-5 and the excess calories from carbohydrates, amino acids, lipids, 6,7 and long-chain polyunsaturated fatty acids have all been implicated. 8 Withholding intravenous fat has led to improvement of IFALD Recently, studies showed that Long-term PN [parenteral nutrition] often leads to intestinal failure associated liver disease (IFALD) and may progress to irreversible liver damage. substitution of part or all of soybean oil based lipid emulsion (SOLE) with fish oil based lipid emulsion (FOLE) resulted in improvement of cholestasis. 7,10-12 SOLE (omega-6:omega-3 ratio of 5.5:1) contains phytosterols, which are known to reduce bile flow. 13 Omega-6 fatty acids are known to be a precursor of pro-inflammatory cytokines 14 implicated in the development of steatosis. The omega- 6:omega-3 ratio is an important regulator of inflammation and a ratio between 1:1 30 DOI: / From Division of Pediatric Gastroenterology, Hepatology and Nutrition (VG, VM); Department of Pharmacy (MT), Sainte-Justine University Hospital, University of Montreal, Montreal, Quebec, Canada. Address correspondence to Veronique Groleau, MD, Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, 3175 Chemin de la Cote Sainte-Catherine, Montreal, PQ, Canada, H3T 1C5; veronique.groleau@umontreal.ca. For reprints and permissions queries, please visit SAGE s Web site at Copyright 2013 The Author(s)

2 vol. 6 no. 1 ICAN: Infant, Child, & Adolescent Nutrition Table 1. Demographic Data of Patients Who Received Fish Oil Based Lipid Emulsion (FOLE) Overall and by Treatment Groups. a Median (Interquartile Range) All (n = 20) Group 1 (n = 15) Group 2 (n = 1) Group 3 (n = 4) Prematurity <35 weeks, n Age at initiation of FOLE, months 1.9 (1.2, 6.2) 1.9 (1.0, 5.7) (1.4, 14.7) Duration of each parenteral nutrition course, days Duration of parenteral nutrition before initiation of FOLE, days 125 (78, 249) 83 (72, 174) (233, 530) 46 (28, 84) 38 (25, 84) (42, 75) Duration of FOLE, days 78 (46, 180) 63 (45, 100) (107, 208) Direct bilirubin at initiation of FOLE µmol/l 58 (39, 76) 55 (37, 76) (61, 61) mg/dl 3.4 (2.3, 4.4) 3.2 (2.2, 4.4) (3.6, 3.6) a Group 1 = soybean oil based lipid emulsion (SOLE) followed by a mixture of SOLE and FOLE. Group 2 = SOLE followed by FOLE monotherapy. Group 3 = mixture of SOLE and FOLE followed by FOLE monotherapy. (similar to breast milk) and 4:1 might be optimal for immunomodulation Omega-3 fatty acids improve bile flow, 4,18 decrease hepatic steatosis 8 and improved the severity of high-fat diet induced liver steatosis in rats. 4,10,19 The American Society of Parenteral and Enteral Nutrition recently published a position paper regarding the clinical role for alternative intravenous fat emulsion. 20 They concluded that evidence for the clinical use of alternative fat emulsions as FOLE is still not clearly defined and further research is needed on the role of FOLE monotherapy or in combination with other oils in IFALD and other chronic inflammatory disorders. The aim of this study was to provide more information about the impact of FOLE on cholestasis and IFALD when used as monotherapy or in combination with SOLE. Methods Medical records of all the patients who received FOLE (Omegaven, Fresenius Kabi, Bad Homburg, Germany, obtained through Health Canada s Special Access Program) for at least 1 month between October 2007 and December 2009 were reviewed. Total and conjugated bilirubin, alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) levels were recorded 4 weeks prior (week 4) to the initiation of FOLE, at initiation of FOLE (week 0), and at 4 weeks (week +4), 8 weeks (week +8), and 24 weeks (week +24) after initiation of FOLE. Enteral and parenteral caloric intakes were documented. Serum essential fatty acids (EFAs) were measured and trieneto-tetraene ratio was obtained every 6 months for patients on long-term PN. Charts were reviewed for other FOLEassociated complications. The protocol was approved by the institutional review board at Sainte-Justine University Hospital, Montreal, Canada. Data Analysis Nonparametric analyses were used exclusively because of the small sample size. Data were reported as medians with interquartile range. Comparisons between groups were performed using the Mann Whitney U test (for 2 groups) or the Kruskal Wallis analysis of variance (for more than 2 groups). Comparisons between time points of the same parameter were performed using Friedman s analysis of variance for repeated measures. Statistical analyses were performed with SPSS 19.0 (IBM Corporation, Somers, NY) and results were considered significant for a P <.05. Results During the study period, 1436 patients received PN at Sainte-Justine University Hospital. Among them, 175 had a direct bilirubin >33 µmol/l (1.9 mg/dl). Thirtyone patients received FOLE, 11 had received FOLE for less than a month and were excluded from further analysis. Diagnosis for the 20 patients studied were as follows: 8 intestinal resection resulting in short bowel syndrome (SBS), 4 intestinal resection without SBS, 3 necrotizing enterocolitis without resection, 2 gastroschisis without resection, 1 intractable diarrhea, 1 diaphragmatic hernia, and 1 immune deficiency. The demographic data are shown in Table 1. PN and FOLE were 31

3 ICAN: Infant, Child, & Adolescent Nutrition February 2014 ongoing for 6 patients at the end of the study. Once FOLE was initiated, patients remained on it until PN was stopped. Conjugated bilirubin levels at week 4 were 22 µmol/l (interquartile range [IQR] = µmol/l) (1.3 mg/dl; IQR = 0.8, 2.9 mg/dl) and increased to a median of 58 µmol/l (IQR = = µmol/l) (3.4 mg/dl; IQR = mg/dl) at week 0. Direct bilirubin levels remained stable at 55 µmol/l (IQR µmol/l) (3.2 mg/ dl; IQR = mg/dl) at week +8 and decreased to a median of 17 µmol/l (IQR = µmol/l) (1.0 mg/dl; IQR = mg/dl) at week +24 for the 6 patients still on PN (P <.05; Figure 1). Post hoc analysis showed that the conjugated bilirubin levels decreased (P <.05) between +4 and +24 weeks. This improvement was associated with a decrease in PN calories (P <.05; Figure 2) and an increase in enteral calories that approached clinical significance (P =.08; Figure 3). Changes in ALT and GGT levels were not significant during the same period. Outcome was different according to the 3 FOLE administration modes. Results of the 3 groups are shown in Figure 4. Group 1 Fifteen patients were on SOLE and were then switched to a 1:1 mixture of the 2 lipid emulsions (SOLE 1 g/kg and FOLE 1 g/kg). Diagnosis included the follwoing: SBS (4), intestinal resection without SBS (4), necrotizing enterocolitis without resection (3), gastroschisis without resection (1), intractable diarrhea (1), diaphragmatic hernia (1), and immune deficiency (1). Five patients demonstrated improvement of their bilirubin levels. They had received FOLE for a median of 10 weeks (IQR = 8-25 weeks) while the 10 patients who showed no improvement in their bilirubin levels had received FOLE for a median of only 5 weeks (IQR = 3-10 weeks; P <.05). Three patients in group 1 were still on FOLE by the end of the study. Group 2 One patient with SBS was on SOLE (1 g/kg) and was switched to FOLE monotherapy (1 g/kg). His direct Figure 1. Bilirubin. Conjugated bilirubin is presented over time (4 weeks prior [ 4 weeks] to initiation of fish oil based lipid emulsion [FOLE], at initiation [0 weeks], and 4 weeks, 8 weeks, and 24 weeks after initiation). Boxplots of conjugated bilirubin (µmol/l) represent the interquartile range, the horizontal lines represent the median, and the outliers are denoted as and extreme outliers as *. The figure shows that direct bilirubin level remained stable until 8 weeks and decreased at 24 weeks for the 6 patients still on parenteral nutrition (P <.05). Figure 2. Parenteral Calories. Parenteral nutrition (PN) calories are presented over time (at the start of fish oil based lipid emulsion [FOLE], and 4 weeks, 8 weeks, and 24 weeks after initiation). Boxplots of parenteral calories (kcal/kg/d) represent the interquartile range, the horizontal lines represent the median, and the outliers are denoted as and extreme outliers as *. The figure shows a reduction in parenteral calories in the 24 weeks following the introduction of FOLE (P <.05). 32

4 vol. 6 no. 1 ICAN: Infant, Child, & Adolescent Nutrition Figure 3. Enteral Calories. Figure 4. Evolution of Bilirubin for the 3 Groups. Enteral nutrition (EN) calories are presented over time (at the start of fish oil based lipid emulsion [FOLE], and 4 weeks, 8 weeks, and 24 weeks after initiation]. Boxplots of enteral calories (kcal/ kg/d) represent the interquartile range, the horizontal lines represent the median, and the extreme outliers are denoted as *. The figure shows the almost significant increase in enteral calories in the 24 weeks following the introduction of FOLE (P =.08). bilirubin level was 411 µmol/l (24.0 mg/ dl) at initiation of FOLE and decreased to 82 µmol/l (4.8 mg/dl) at week 24 while still on PN. Group 3 Four patients received a mixture of both lipid emulsions (SOLE 1 g/kg and FOLE 1 g/kg) and were switched to FOLE monotherapy (1 g/kg). Three had SBS and 1 had a gastroschisis without resection. They improved their bilirubin only after discontinuation of SOLE while remaining on FOLE monotherapy. The only adverse effect of FOLE was EFA deficiency. One patient from group 3 had a triene-to-tetraene ratio of without any clinical manifestation. No other complication was reported. Discussion There was an overall improvement of cholestasis in patients receiving FOLE. The decrease in bilirubin was significant 24 weeks after introduction of FOLE for the 6 patients who were still on PN. The greatest improvement was observed in the patients for whom SOLE was stopped (groups 2 and 3) while only a third of group 1 had a decrease in bilirubin levels on a SOLE/FOLE mixture. Three major studies 9,11,21 reported complete resolution of hyperbilirubinemia with FOLE. The study by Diamond et al 9 showed resolution of cholestasis with a 1:1 mixture of SOLE and FOLE in a median of 24 weeks (IQR = 7-37 weeks) in 9/12 patients. Gura et al 11 used FOLE monotherapy and had resolution of cholestasis in 9.4 weeks (IQR = weeks) in 11/18 patients. In the study by Puder et al, 21 a resolution of the cholestasis was observed in 19/42 infants with SBS treated with FOLE monotherapy in a median time of 11.7 weeks (IQR = weeks). Both the use of FOLE and the decrease in SOLE might play a strategic role in the improvement of cholestasis. Patients in whom cholestasis improved had received FOLE for a significantly longer time period, Conjugated bilirubin (µmol/l) is presented over time (4 weeks prior [ 4 weeks] to initiation of fish oil based lipid emulsion [FOLE], at initiation [0 weeks], and 4 weeks, 8 weeks, and 24 weeks after initiation). Group 1 represents the 15 subjects who were on soybean oil based lipid emulsion (SOLE) followed by a mixture of SOLE and FOLE. Group 2 represents the subject on SOLE followed by FOLE monotherapy. Group 3 represents the 4 subjects on a mixture of SOLE and FOLE followed by FOLE monotherapy. The figure demonstrates that after the introduction of FOLE only group 1, which was still receiving SOLE, had a conjugated bilirubin that kept rising, contrarily to groups 2 and 3. A decrease in conjugated bilirubin was finally observed in group 1, but more than 8 weeks after the initiation of FOLE (P <.05). suggesting that receiving FOLE for a short period of PN may not be as beneficial as for long-term PN. Although these data regarding PN-associated cholestasis are encouraging, there was no significant change in ALT and GGT levels. This is in keeping with prior studies 9,22 suggesting that normalization of bilirubin level does not necessarily imply resolution of IFALD. The fact that a significant decrease in PN calories and an increase in enteral calories concurred with the improvement of cholestasis remains a confounding factor. The total amount of intravenous (IV) fat is another important factor that affects IFALD. Group 1 received a total of 2 g/kg of IV fat while group 2 received only 1 g/ kg of IV fat and group 3 went from 2 to 1 g/kg fat. Part of the improvement 33

5 ICAN: Infant, Child, & Adolescent Nutrition February 2014 documented in group 3 may be secondary to the reduction in total IV fat. This study had other limitations as it was a retrospective study of a small sample, especially for group 2, which had only one subject. It would also be important in future studies to look at the impact of sepsis episodes and surgeries. Only one patient was EFA deficient without any clinical manifestations. According to Gura et al, 23 FOLE monotherapy should supply sufficient arachidonic acid to prevent EFA deficiency. There was no burr cell anemia among this cohort but a case report has been published. 24 There is also a theoretical concern of coagulopathy although clinical experience does not support it. 11,23 Conclusion In our population, there was a decrease in direct bilirubin levels 24 weeks after the initiation of FOLE; this however was associated with a decrease in parenteral calories. FOLE monotherapy was more effective than a mixture of SOLE and FOLE when treating preexisting IFALD, and the improvement in bilirubin was seen earlier with FOLE monotherapy treatment. To prevent or treat IFALD, the judicious use of SOLE and FOLE is recommended with minimization of lipids when possible. A randomized controlled trial comparing FOLE to a standard SOLE would enlighten us about the efficacy of FOLE while controlling for potential confounders as advancement in enteral feeding. Author Note The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/ or publication of this article. References 1. Koletzko B, Goulet O. Fish oil containing intravenous lipid emulsions in parenteral nutrition-associated cholestatic liver disease. Curr Opin Clin Nutr Metab Care. 2010;13: Kelly DA. Liver complications of pediatric parenteral nutrition epidemiology. Nutrition. 1998;14: Iyer KR, Spitz L, Clayton P. 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