Novel Insights from Clinical Practice

Neonatology 2010;98:348353 DOI: 10.1159/000316067

Received: April 30, 2010 Accepted after revision: May 31, 2010 Published online: October 27, 2010

Early Enteral Fat Supplementation with Microlipid and Fish Oil in the Treatment of Two Premature Infants with Short Bowel
QingYang a CherrieD.Welch a KathleenAyers b CharlesTurner c ThomasPranikoff c

a c

Division of Neonatology, Department of Pediatrics, b Clinical Nutrition Department, and Pediatric Surgery Service, Wake Forest University Health Sciences, Winston-Salem, N.C., USA

Established Facts
Premature infants with short bowel are at a distinct advantage for intestinal adaptation due to their continued and rapid growth of intestine. Late addition of Microlipid to diet decreased ostomy output and improved weight gain in infants with ostomy, and Omegaven (intravenous fish oil emulsion) has been used to treat parenteral nutrition-associated cholestasis in infants with short bowel syndrome.

Novel Insights
Premature infants with short bowel syndrome may require more dietary fat to adequately supply the substrate needed not only for normal growth of bowel but for bowel adaptation, and thus current clinical practice of giving a relatively low-fat diet to these infants may not meet their high metabolic needs. Early enteral supplementation with Microlipid and fish oil may improve bowel adaptation and growth, reduce the use of parenteral nutrition, and prevent parenteral nutrition-associated cholestasis.

Key Words Enteral fat Fish oil Microlipid Premature infant Short bowel syndrome Long-chain polyunsaturated fatty acids

Abstract The infusion of Intralipid is a main risk factor for parenteral nutrition-associated cholestasis in infants with short bowel syndrome. Early provision of enteral fat to reduce the use of Intralipid while providing adequate fat for the growth of infants with short bowel has not been reported. We present 2 cases of premature infants with short bowel who received

early supplementation of enteral Microlipid and fish oil. This approach allowed us to discontinue Intralipid shortly after initiating feedings. The infants tolerated Microlipid/fish oil well without adverse reactions, had appropriate weight gain and ostomy output. They underwent bowel reanastomosis 3 weeks after enteral feeding began, and were discharged on full oral feedings. In case 1, the infant did not develop parenteral nutrition-associated cholestasis; in case 2, cholestasis had developed before initiating feeds, but was not aggravated by enteral fat and was improving prior to discharge. Copyright 2010 S. Karger AG, Basel

2010 S. Karger AG, Basel 16617800/10/09840348$26.00/0 Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Accessible online at: www.karger.com/neo

Qing Yang, MD, PhD Division of Neonatology, Department of Pediatrics Wake Forest University Health Sciences Medical Center Boulevard, Winston-Salem, NC 27157 (USA) Tel. +1 336 716 8687, Fax +1 336 716 2525, E-Mail qyang@wfubmc.edu

Introduction

Case Reports
Case 1 A 336/7-week gestational age (GA) infant with a birth weight of 1,568 g underwent a small bowel resection for a volvulus involving the distal three-fourths of the ileum at 36 h of life. A proximal ileostomy was created and 68 cm of small intestine and the colon remained. Continuous gastric enteral feeding using human milk was initiated 6 days after surgery. Enteral lipid of ML (Novartis) (0.5 g/kg/day) followed by FO (Major Pharmaceuticals, Item code 257063) (0.5 g/day) were administered over the subsequent 2 days. The ML was gradually increased to 2 g/day, and enteral feedings steadily increased to approximately 80 ml/kg/day while PN decreased accordingly. The ostomy output ranged from 818 ml/kg/ day or 737% of intake. The IL (Kabi Pharmacia) was discontinued after 8 days of feeding. The infants weight gain averaged 28 g/day during the feeding. Reanastomosis of the bowel was performed when the infants weight was 2,066 g. At the time of surgery, the length of the remaining small intestine was measured at 84 cm, representing an interval growth of 16 cm. After reanastomosis, the ML and FO were resumed when the feedings with human milk were restarted, and the IL was discontinued 5 days thereafter. The ML and FO were gradually increased to 4.8 and 0.75 g/day, respectively, and the PN was discontinued on day of life (DOL) 93. The infant was discharged on DOL 97 on full oral feeding. The conjugated bilirubin, liver function tests, electrolytes, platelet count, and triglyceride level were all within normal limits, and there were no infections as well during the hospital course. Case 2 A 275/7-week GA infant with a birth weight of 1,090 g underwent massive jejunoileal resection due to necrotizing enterocolitis (NEC) with bowel perforation on DOL 19. A jejunostomy was created and 32 cm of small intestine and the colon remained. Continuous gastric enteral feeding using human milk was started 2 weeks after surgery followed by ML (1 g/kg/day) and then FO (0.5 g/day) in the subsequent day. The ML and FO were gradually increased to 4.2 and 0.75 g/day, respectively. Enteral feedings were steadily increased to 50 ml/kg/day while the PN was decreased accordingly. Ostomy output ranged from 7 to 19 ml/kg/day or 1571% of intake. The IL was discontinued after 9 days of feeding. The average weight gain was 26 g/day during feeding. Bowel reanastomosis was performed when the infant weighed 1,870 g. At the time of surgery, the length of the remaining small intestine was measured at 54 cm, representing an interval growth of 22 cm. The ML and FO were resumed when the feeds were restarted with mainly elemental formula, and the IL was discontinued 4 days thereafter. The ML and FO were gradually increased to 5.6 and 1 g/day, respectively, and the PN was discontinued on DOL 76. The infant was discharged on DOL 86 on oral feeding ad libitum. The serum electrolytes, platelet count, and triglyceride level were within normal limits, and there were no infections during the feeding periods. Before enteral feeding was initiated, the infant had developed PN-associated cholestasis. However, the conjugated bilirubin was not aggravated by enteral fat and was improving prior to discharge. Cases 1 and 2 are summarized in table1, and their daily energy intakes and weight gain before reanastomosis are displayed in figure 1.

Cholestasis is a major complication of prolonged parenteral nutrition (PN) in neonates [1]. This disorder can lead to liver failure, and is associated with a high mortality rate in infants with short bowel syndrome (SBS) [2]. The etiology is multifactorial and includes the infusion of intravenous lipid, Intralipid (IL). The predominantly soy-based IL contains phytosterols that displace cholesterol from lipid pools and increase the oxidant load on the liver [3]. Lipid infusion exceeding 1 g/kg/day is associated with an increased risk of liver disease [4]. In addition, a study showed that premature neonatal piglets developed fatty liver after infusion of PN supplemented with IL for 7 days [5]. Recently, a low dose (1.0 g/kg/day) of parenteral fish oil (FO) emulsion, Omegaven, has been used as the sole source of lipid for the treatment of infants with PN-associated cholestasis [6]. However, management of SBS in premature infants with either IL or Omegaven at 1 g/kg/day falls far short of the fat intake of 57 g/kg/day recommended by the American Academy of Pediatrics for the growth and development of a well preterm infant [7]. Furthermore, whether the enteral FO could play the same role as Omegaven in treating and/or preventing PNassociated cholestasis is unknown. Enteral nutrition is the primary therapy for SBS. Experimental evidence suggests that diets high in fats [8], especially long-chain fatty acids [9], and the long-chain polyunsaturated fatty acids (LCPUFA) [10, 11] are more effective in stimulating intestinal adaptation after extensive small bowel resection. However, there is scant information regarding the translation of these research findings into clinical practice. One retrospective study showed that late (at mean of 50 days after ostomy) addition of Microlipid (ML) to the diet decreased ostomy output and improved weight gain in infants with ostomy [12]. We hypothesize that early supplementation of infants who have short bowel with enteral fat will improve bowel adaptation and infant growth, reduce the need for PN including IL, and prevent PN-associated cholestasis. Here we present case reports of 2 premature infants with short bowel who received this novel approach. We used ML as the source of n6 polyunsaturated fatty acid (PUFA) and FO as the source of n3 LCPUFA to preserve a proper ratio of n6/n3 PUFA [13].

Early Supplementing Short Bowel Infants with ML and Fish Oil

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Case 1 150 Total PN EN Wt. 2.0

120 1.9

kcal/kg/day

1.7 60 1.6 30 1.5

0 1 3 5 7 9

1.4 11 13 Feeding days 15 17 19 21

Case 2 150 Total PN EN Wt. 1.8

120 1.7 kcal/kg/day Weight (kg)

90 1.6 60 1.5 30 1.4 0 1 3 5 7 9 11 Feeding days 13 15 17

Fig. 1. Daily total, parenteral and enteral

energy intake and weight gain before reanastomosis in case 1 (a) and case 2 (b). The total energy intake and energy intake from parenteral nutrition (PN) and enteral nutrition (EN) are expressed as kcal/kg/ day in the left y-axis. Daily weight (Wt.) is expressed as kg in the right y-axis and displayed by a bold dashed line.

Discussion

SBS occurs following significant resection of small bowel, resulting in malabsorption and malnutrition. In newborn infants, NEC and midgut volvulus are most fre350
Neonatology 2010;98:348353

quently responsible for SBS [14]. The main goal of treatment in SBS is to optimize the intestinal adaptation by attempting to maximize enteral nutrition while minimizing PN. Intestinal adaptation is a compensatory physiological response that begins 2448 h after resection of
Yang /Welch /Ayers /Turner /Pranikoff

Weight (kg)

90

1.8

Table 1. Summary of cases 1 and 2

Case 1 GA, weeks/birth weight, g 336/7/1,568 Cause of short bowel midgut volvulus Onset of short bowel DOL 3 Location of enterostomy proximal ileostomy Residual small bowel, cm 68 Ileocecal valve/colon lost/intact During the feeding period before reanastomosis Feeding start POD 7 (with human milk) ML/FO start POD 9/10 Maximum ML/FO, g/day 2.0/0.5 Total protein intake, g/kg/day 2.94.4 Total fat intake, g/kg/day 1.95.6 Maximum use of IL, g/kg/day 2.0 Days to taper off IL 8 Average weight gain, g/day 28 Weight at reanastomosis, g 2,066 Conjugated bilirubin, mg/dl 0.60.7 During the feeding period after reanastomosis, before discharge Feeding start POD 5 (with human milk) ML/FO start POD 10/10 Maximum ML/FO, g/day 4.8/0.75 Days to taper off IL/HAL 5/55 Days to full feeding, 150 ml/kg/day 23 Daily stool 39 Average weight gain, g/day 16 Weight at discharge, g 3,078 Discharge age (DOL)/nutrition 97/full oral feeding Conjugated bilirubin, mg/dl 0.3
1

Case 2 275/7/1,090 NEC/perforation DOL 19 jejunostomy 32 present/intact POD 15 (with human milk) POD 18/19 4.2/0.75 2.74.4 1.05.2 1.5 9 26 1,870 3.815.3 POD 9 (with Neocate) POD 12/10 5.6/1.0 4/17 24 27 19 2,497 86/full oral feeding ad libitum 4.35.8 (5.02)

POD = Postoperative day; HAL = hyperalimentation. Conjugated bilirubin level before feeding start. 2 Conjugated bilirubin level before discharge.

bowel and is important in restoring the digestive and absorptive capacity of the residual intestine [15]. Animal studies show that enteral feeding contributes greatly to intestinal adaptation [16]; among the macronutrients, long-chain fatty acids [9], especially the LCPUFAs [10, 11], are most beneficial in stimulating this response. In the rat model, a low-fat diet impaired, whereas a high-fat diet promoted post-resection intestinal adaptation [8]. Neonates, especially premature human neonates, are at a distinct advantage for intestinal adaptation after resection compared with adults [17] due to their continued and rapid growth of intestine [18]. Given their continued maturation, premature infants with SBS might require more dietary fat to adequately supply the substrate needed not only for normal growth of bowel but also for bowel adaptation. However, the nutritional needs suggested by these
Early Supplementing Short Bowel Infants with ML and Fish Oil

research findings [811] are at odds with current widespread clinical practice. Infants with SBS are often given elemental formula containing less fat and less LCPUFA than human milk due to a concern of fat malabsorption in SBS. In actuality, fats, especially the LCPUFA, as compared to carbohydrate and protein, are very large molecules that create the least osmotic load and contain the highest calorie density. Thus they are unlikely to cause osmotic diarrhea and hence increase the amount of calories absorbed [19]. The two main categories of PUFA, n3 and n6 PUFA, are essential fatty acids. ML is composed of 50% safflower oil in which the major component fatty acid is linoleic acid (75%), a n6 PUFA. FO is the main source of anti-inflammatory n3 LCPUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Each gram
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of FO used in this report contains 90 mg of EPA and 110 mg of DHA. In our standard practice, ML is usually given to provide extra energy to infants who already take a high-calorie formula but still have poor weight gain. In the 2 cases presented, we started ML in the early stage of enteral feeding, and we add FO in order to balance the n6/n3 PUFA ratio [12] and provide anti-inflammatory n3 EPA and DHA as well. In addition, in a rat SBS model, dietary FO, compared with other fat sources, not only markedly increased mucosal weight, DNA and protein, but also significantly enhanced the plasma level of peptide YY [11], a hormone that slows motility and lengthens transit time, resulting in increased mucosal contact with nutrients, and thereby increasing intestinal adaptation [20]. In this report, the starting dose of FO is based on the human uterine accretion of DHA (50 mg/ day) [21], and the maximal dose is based on the fact that DHA ^315 mg/day appears to be safe in breast-fed infants 16 months of age who solely consume human milk with a DHA content at the high end of normal (1.0% total fatty acids) [22]. Recently, a high-DHA preterm formula or high-DHA human milk (approximately 1.0% total fatty acids) had been safely given to premature infant born before 33 weeks gestation in a randomized controlled trial (DINO trial) [23]. By calculation based on consumption of 150 ml/kg/day, the daily DHA (mg/day) provided from FO and human milk or elemental formula in this report was close to but still less than the amount consumed by premature infants in DINO trial.

The 2 premature infants received this novel nutritional approach after extensive small bowel resection. Both infants tolerated the early enteral supplementation of ML/FO well without adverse reactions, allowing us to rapidly discontinue the use of IL, which is considered as one of major factors contributing to PN-associated cholestasis [3]. In case 1, the infant did not develop cholestasis; in case 2, the cholestasis had developed before initiating feeds, but was not aggravated by enteral fat and was improving prior to discharge. Due to early supplementation of enteral fat, the total daily fat administration was not compromised by eliminating the IL before they reached full enteral feeds. Prior to reanastomosis, the total fat the infants received from enteral supplementation and human milk, without IL, averaged 4.8 g/kg/day in case 1, and 4.7 g/kg/day in case 2. The infants tolerated feeds well, had appropriate weight gain and ostomy output. They underwent bowel reanatomosis 3 weeks after enteral feeding began, and were discharged on full oral feeding at 12 and 9 weeks, respectively, from the initial surgery. In addition, the infants had no infections while on enteral feedings. The outcomes of these 2 premature infants with short bowel who received this novel approach are promising when retrospectively compared with our historic SBS cases, but concurrent control data are needed. Therefore, we are currently conducting a randomized pilot clinical trial to further evaluate this strategy in the nutritional support of infants with SBS.

References
1 Buchman AL: Complications of long-term home total parental nutrition: their identification, prevention and treatment. Dig Dis Sci 2001;46:118. 2 Quirs-Tejeira RE, Ament ME, Reyen L, Herzog F, Merjanian M, Olivares-Serrano N, Vargas JH: Long-term parenteral nutritional support and intestinal adaptation in children with short bowel syndrome: a 25-year experience. J Pediatr 2004;145:157163. 3 Wessel JJ, Kocoshis SA: Nutritional management of infants with short bowel syndrome. Semin Perinatol 2007;31:104111. 4 Cavicchi M, Beau P, Crenn P, Degott C, Messing B: Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. Ann Intern Med 2000; 132: 525532. 5 Hyde MJ, Amusquivar E, Laws J, et al: Effects of lipid-supplemented total parenteral nutrition on fatty liver disease in a premature neonatal piglet model. Neonatology 2008; 93: 7786. 6 Gura KM, Lee S, Valim C, Zhou J, Kim S, Modi BP, Arsenault DA, Strijbosch RA, Lopes S, Duggan C, Puder M: Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 2008;131:e678e686. 7 Feeding the infant: nutritional needs of the preterm infant; in Kleinmann RE (ed): Pediatrics Nutrition Handbook, ed 6. Elk Grove Village, American Academy of Pediatrics, 2008, pp 7985. 8 Sukhotnik I, Shiloni E, Krausz MM, Yakirevich E, Sabo E, Mogilner J, Coran AG, Harmon CM: Low-fat diet impairs post-resection intestinal adaptation in a rat model of short bowel syndrome. J Pediatr Surg 2003;38:11821187. 9 Vanderhoof JA, Garandjean CJ, Kaufman SS, Burkley KT, Antonson DL: Effect of high percentage medium-chain triglyceride diet on mucosal adaptation following massive bowel resection in rats. JPEN J Parenter Enteral Nutr 1984;8:685689. 10 Kollman KA, Lien EL, Vanderhoof JA: Dietary lipids influence intestinal adaptation after massive bowel resection. J Pediatr Gastroenterol Nutr 1999;28:4145.

352

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Yang /Welch /Ayers /Turner /Pranikoff

11 Vanderhoof JA, Park JHY, Herrington MK, Adrian TE: Effects of dietary menhaden oil on mucosal adaptation after small bowel resection in rats. Gastroenterology 1994; 106: 9499. 12 Malcolm WF, Lenfestey RW, Rice HE, Rach E, Goldberg RN, Cotten CM: Dietary fat for infants with enterostomies. J Pediatr Surg 2007;42:18111815. 13 Simopoulos AP: The importance of the ratio of 6/ 3 essential fatty acids. Biomed Pharmacother 2002;56:365379. 14 Zieler MM: Short bowel syndrome in infancy. Etiology and management. Clin Perinatol 1986;13:167173.

15 Vanderhoof JA: Short bowel syndrome in children. Curr Opin Pediatr 1995;7:560568. 16 Feldman EJ, Dowling RH, McNaughton J, Peters TJ: Effects of oral versus intravenous nutrition on intestinal adaptation after small bowel resection in the dog. Gastroenterology 1976;70:712719. 17 Caniano DA, Starr J, Ginn-Pease ME: Extensive short bowel syndrome in neonates: outcome in the 1980s. Surgery 1989; 105: 119 124. 18 Touloukian RJ, Smith GJW: Normal intestinal length in preterm infants. J Pediatr Surg 1983;18:720723. 19 Vanderhoof JA: Short bowel syndrome. Clin Perinatol 1996;23:377386.

20 Adrian TE, Savage AP, Fuessl HS, et al: Release of peptide YY after resection of small bowel, colon, or pancreas in man. Surgery 1987;101:715719. 21 Clandinin MT, Chappell JE, Eim T, et al: Fatty acid utilization in perinatal de novo synthesis of tissues. Early Hum Dev 1981;5:355 366. 22 Lien EL: Toxicology and safety of DHA. Prostaglandins Leukot Essent Fatty Acids 2009;81:125132. 23 Majrides M, Gibson RA, McPhee AJ, et al: Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA 2009; 301:175182.

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