Parenteral Nutrition: Complications of Long-Term Use in Pediatric Patients

Cholestasis is a serious complication of long-term parenteral nutrition use.

Introduction and Background

Parenteral nutrition (PN) is a life-saving therapy for patients unable to meet nutritional needs by mouth.¹ Today, over 30,000 patients depend on long-term PN and more than 350,000 patients receive PN on a yearly basis.² Although these figures represent patients of all ages, many pediatric patients depend on PN for survival, particularly those with intestinal failure/short-bowel syndrome (SBS).

PN is a method of intravenous (IV) delivery of nutrients, specifically macronutrients (amino acids, dextrose, IV fat emulsion [IVFE]), micronutrients (vitamins, minerals, trace elements and electrolytes), and fluids that are individually tailored to meet a patient’s daily nutritional requirements.³ Although PN has revolutionized the care of pediatric patients unable to meet nutritional requirements enterally, chronic use may lead to several complications including nutritional deficiencies, electrolyte abnormalities, infections, metabolic bone disease, and PN-associated cholestasis (PNAC).

PNAC is one of the most challenging morbid complications associated with PN. The incidence of PNAC ranges from 7.4% to 84%; this wide range is due to the heterogeneity of study subjects, differences in definitions of PNAC, and variation of composition and duration of PN therapy described in the literature.^4-6 When PNAC develops, it is a predictor of mortality and morbidity; up to one-third of surgical neonates who develop PNAC are at risk of mortality, and in patients with SBS, PNAC is the greatest risk factor for mortality.

PNAC is clinically characterized by elevations in liver enzymes. Prolonged PN use (>2 weeks) is associated with cholestasis that may progress to liver failure if not treated appropriately.^7,8 Biochemical markers of PNAC include elevations is serum gamma-glutamyl transpeptidase and serum bilirubin. Serum direct (conjugated) bilirubin >2 mg/dL is commonly used as a marker of PNAC.^9,10 Signs and symptoms may also include jaundice, hepatosplenomegaly, and ascites.

The causes of PNAC are multifactorial and include prematurity, lowbirth weight, prolonged duration of PN, lack of enteral feeding, development of sepsis, bacterial overgrowth, and the presence of SBS.^10,11 An additional and independent risk factor is the administration of soybean-based IVFE at standard doses (up to 3 g/kg/day). Soybean-based IVFE is the only IVFE approved by the FDA for use in pediatric patients.¹² The exact mechanism by which soybean-based IVFE is believed to contribute to PNAC is unknown, but several mechanisms have been proposed, including the presence and proinflammatory effects of omega-6 fatty acids; the presence of phytosterols, which can impair bile drainage; a direct effect on the hepatocytes; and cell membrane peroxidation.^13-16

Nutrition support providers are thus caught between a rock and a hard place. IVFE is a critical component of PN solutions due the provision of calories and energy and its role in preventing the development of essential fatty acid deficiency (minimum dose required is 0.5-1 g/kg/day). However, providing soybean- based IVFE is an independent risk factor for the development of PNAC. While IVFE cannot be removed from PN solutions, there are 2 approaches to managing this conundrum that will be discussed: (1) the use of alternative source IVFE and (2) soybean-based IVFE dose minimization.

Alternative-Source IVFE

Although not approved for use in the United States in pediatric patients, olive oil—containing fat emulsions have been evaluated in the setting of PNAC. A prospective, randomized, double-blind trial in patients younger than 10 years of age on PN for at least 3 months showed a similar incidence of PNAC in patients who received an olive oil–based IVFE (1.92 ± 0.17 g/kg/day) compared with those who received soybean-based IVFE (1.69 ± 0.15 g/kg/ day).¹⁷ Two similar studies conducted in neonates and infants also showed similar incidences of PNAC in those who received olive oil—based IVFE compared with those who received soybean-based products.^18,19

All 3 of these studies have limitations, namely short study duration, small numbers of patients, and study design. Although olive oil—based IVFE provides an interesting alternative to soybean-based fat emulsions, the presence of phytosterols and omega-6 fatty acids may still be problematic to the liver, even though the content of these is less than what is found in soybean-based IVFE. Further research is needed with these emulsions to fully understand the potential benefit they may have in the PNAC setting.

Another alternative source emulsion is the composite emulsion SMOFlipid.²⁰ Also not approved for use in the United States, this is a combination of soybean oil, medium-chain triglycerides, olive oil, and fish oil. In a single-center, double-blind, randomized prospective cohort, pediatric patients 5 months to 11 years of age received either SMOFlipid (2 g/kg/day, 4-5 times per week) or soybean-based IVFE (2 g/kg/day, 4-5 times per week).²¹ The patients receiving SMOFlipid experienced a decrease in total bilirubin over the course of the 29-day study, whereas those receiving soybean-based IVFE had an increase in their total bilirubin (P <.01). The benefit of SMOFlipid has also been demonstrated in several case series.^22-24 These favorable results indicated that SMOFlipid may play a beneficial role in the management of PNAC, although long-term effects remain unknown. The benefits seen are theorized to be due to the decreased amounts of phytosterols and omega-6 fatty acids; the addition of omega-3 fatty acids from the fish oil component, which may have anti-inflammatory properties; or both.

The fish oil—based fat emulsions contain mostly omega-3 fatty acids. Additionally, higher levels of alphatocopherol, an antioxidant, are present. Taken together, these components may be responsible for the anti-inflammatory properties and purported beneficial effects of fish oil–based emulsions in the setting of PNAC.^25-27

Fish oil—based emulsions have been shown to be beneficial in reversing PNAC in several case reports as well as small cohort studies.^28-30 In an openlabel, prospective, cohort study, infants predicted to need a minimum of 30 days of PN who developed PNAC were switched to fish oil at a dose of 1 g/kg/day and compared with a cohort that remained on soybean-based IVFE at a dose of 1 to 4 g/kg/day.³¹ Reversal of cholestasis occurred in 45% of the patients receiving fish oil compared with 4.1% of those receiving soybean-based IVFE (P <.0001). Further, the risk of death and the need for liver transplantation were also lower in the fish oil group. These results have been corroborated by several other studies.^32,33

Although fish oil— based emulsions show promise in reversing PNAC, data are limited by study design, small sample sizes, short duration and, importantly, by the fact that the studies use a reduced dose of fish oil (1 g/kg/day). It is unknown whether the positive effects seen correspond to the presence of omega-3 fatty acids, the reduced dose, or both. Fish oil–based fat emulsions are not approved for use in the United States but can be obtained through compassionate-use protocols.

Soybean-Based Fat Emulsion Minimization

As the above fat emulsions are not readily available in the United States, many centers have implemented dose-minimization techniques with the goal of maintaining growth and development, preventing the development of essential fatty acid deficiency, and reducing the risk of PNAC. Soybean-based IVFEs are usually dosed at 2 to 3 g/kg/day; dose-minimization techniques involve dosing at ≤1 g/kg/day.²⁶

The benefit of dose minimization was demonstrated in animals as well as in adults in the early 1980s,^34,35 although it was not until 2000 that it was first described in pediatric patients.³⁶ Since then, the benefit of dose minimization has been demonstrated for the treatment of PNAC.

In a single-institution prospective study with a matched historical cohort, infants with PNAC were transitioned from a standard dose (2-3 g/kg/day) to a minimized dose (1 g/kg/day twice weekly) and compared with a wellmatched historical control that continued to receive the standard dose.³⁷ Infants who received the reduced dose experienced a significant decrease in direct bilirubin over the course of the study compared with those who received standard dosing (P = .0017). Forty-two percent achieved direct bilirubin <2.5 mg/dL compared with 10% in the standard group (P = .013). Importantly, some patients in the study developed a mild essential fatty acid deficiency that was reversed when the dose was increased to 1 g/kg/day 3 days per week. As such, some institutions now use a dose of 1 g/kg/day thrice weekly for the treatment of PNAC once it develops.

Dose reduction has also been investigated for the prevention of PNAC. Several retrospective studies and 1 small prospective pilot study have been published evaluating a dose of 1 g/kg/day compared with standard dosing for the prevention of PNAC with positive results.^14,38,39 However, data are limited by retrospective study design, small sample size, short duration, and lack of long-term follow-up.

Whereas soybean-based fat emulsion minimization strategies appear to be efficacious for both prevention and treatment of PNAC, there are several unanswered questions regarding optimal timing of dose reduction; ideal dosing strategy; long-term data, specifically on neurodevelopmental followup; and comparative efficacy with the alternative fat emulsions.^40,41

Conclusion

PNAC is a serious problem affecting pediatric patients who depend on longterm PN. The uses of alternative IVFE and/or soybean-based IVFE dose minimization appear to be efficacious for the management of PNAC. However, data supporting either approach rely mostly on retrospective or uncontrolled studies, therefore limiting the strength of supporting evidence. The American Society for Parenteral and Enteral Nutrition (ASPEN) has called for more research in this field. ASPEN recognizes soybean-based IVFE dose minimization as a reasonable approach to managing PNAC in patients with intestinal failure; however, more information is needed regarding the olive oil, fish oil, and composite fat emulsions before recommendations can be made, especially since these products are not approved for use in the United States.⁴² Expert opinion holds that both the use of alternative IVFE and soybean- based IVFE dose minimization are superior to conventional therapy and that similar estimates of efficacy between the 2 are expected.⁴³ Before conclusions can be drawn regarding either approach, comparative data from well-designed studies are needed. In addition, expansion of available IVFE products in the United States is necessary.

Dr. Blackmer is an assistant professor of pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences and a clinical pharmacy specialist at Children’s Hospital Colorado. She has practice and research interests in fluids, electrolytes, and nutrition and is particularly interested in investigating complications associated with the long-term administration of parenteral nutrition. Additionally, she has practice and research interests in the care of chronically ill children and children with medical complexity.

References

• Suita S, Yamanouchi T, Masumoto K, Ogita K, Nakamura M, Taguchi S. Changing profile of parenteral nutrition in pediatric surgery: a 30-year experience at one institute. Surgery. 2002;131(suppl 1):S275-S282.
• HCUPnet. Agency for Healthcare Research and Quality website. http://hcupnet.ahrq.gov.
• Btaiche IF, Khalidi N, Kovacevich DS, eds. The University of Michigan Hospital and Health Centers Parenteral and Enteral Nutrition Manual. Ann Arbor, MI: The University of Michigan; 2010.
• Kelly DA. Liver complications of pediatric parenteral nutrition—epidemiology. Nutrition. 1998;14(1):153-157.
• Koseesirikul P, Chotinaruemol S, Ukarapol N. Incidence and risk factors of parenteral nutrition-associated liver disease in newborn infants. Pediatr Int. 2012;54(3):434-436. doi: 10.1111/j.1442-200X.2012.03627.x.
• Duro D, Mitchell PD, Kalish LA, et al. Risk factors for parenteral nutrition—associated liver disease following surgical therapy for necrotizing enterocolitis: a Glaser Pediatric Research Network Study. J Pediatr Gastroenterol Nutr. 2011;52(2):595-600. doi: 10.1097/MPG.0b013e31820e8396.
• Nanji AA, Anderson FH. Sensitivity and specificity of liver function tests in the detection of parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr. 1985;9(3):307-308.
• Beath SV, Booth IW, Murphy MS, et al. Nutritional care and candidates for small bowel transplantation. Arch Dis Child. 1995;73(4):348-350.
• Vileisis RA, Inwood RJ, Hunt CE. Laboratory monitoring of parenteral nutrition-associated hepatic dysfunction in infants. JPEN J Parenter Enteral Nutr. 1981;5(1):67-69.
• Btaiche IF, Khalidi N. Parenteral nutrition-associated liver complications in children. Pharmacotherapy. 2002;22(2):188-211.
• Blackmer AB, Btaiche IF, Arnold AA, Teitelbaum DH. Parenteral nutrition-associated liver disease in pediatric patients: strategies for treatment and prevention. In: Murray KF, Horslen S, eds. Diseases of the Liver in Children. New York, NY: Springer Science and Business Media; 2014:327-349.
• Kumpf VJ. Parenteral nutrition-associated liver disease in adult and pediatric patients. Nutr Clin Pract. 2006;21(3):279-290.
• Tillman EM. Review and clinical update on parenteral nutrition—associated liver disease. Nutr Clin Pract. 2013;28(1):30-39. doi: 10.1177/0884533612462900.
• Nehra D, Fallon EM, Carlson SJ, et al. Provision of a soy-based intravenous lipid emulsion at 1 g/kg/day does not prevent cholestasis in neonates. J Parenter Enteral Nutr. 2013;37(4):498-505. doi: 10.1177/0148607112453072.
• Rangel SJ, Calkins CM, Cowles RA, et al. Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review. J Pediatr Surg. 2012;47(1):225-240. doi: 10.1016/j.jpedsurg.2011.10.007.
• Kurvinen A, Nissinen MJ, Andersson S, et al. Parenteral plant sterols and intestinal failure-associated liver disease in neonates. J Pediatr Gastroenterol Nutr. 2012;54(6):803-811. doi: 10.1097/MPG.0b013e3182474118.
• Goulet O, de Potter S, Antebi H, et al. Long-term efficacy and safety of a new olive oil-based intravenous fat emulsion in pediatric patients: a double-blind randomized study. Am J Clin Nutr. 1999;70(3):338-345.
• Wang Y, Zhou KJ, Tang QY, et al. Effect of an olive oil-based lipid emulsion compared with a soybean oil-based lipid emulsion on liver chemistry and bile acid composition in preterm infants receiving parenteral nutrition: a double-blind, randomized trial. JPEN J Parenter Enteral Nutr. 2015. pii: 0148607114566853.
• Teng J, Arnell H, Bohlin K, Nemeth A, Fischler B. Impact of parenteral fat composition on cholestasis in preterm infants. J Pediatr Gastroenterol Nutr. 2015;60(6):702-707. doi: 10.1097/MPG.0000000000000739.
• SMOFlipid [product monograph]. Mississauga, Ontario, Canada: Fresenius Kabi Canada; 2012.
• Goulet O, Antebi H, Wolf C, et al. A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2010;34(5):485-495. doi: 10.1177/0148607110363614.
• Muhammed R, Bremner R, Protheroe S, Johnson T, Holden C, Murphy MS. Resolution of parenteral nutrition—associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion. J Pediatr Gastroenterol Nutr. 2012;54(6):797-802. doi: 10.1097/MPG.0b013e3182447daf.
• Ferreira N, Falconer J, Harley C, Rawat D, Fell J, Koglmeier J. Improved serum bilirubin with SMOF lipid in children with intestinal failure on long term parenteral nutrition. Paper presented at: British Society of Paediatric Gastroenterology, Hepatology and Nutrition Winter Meeting; January 28-30, 2009; Sheffield, England.
• Anish A, Lawson A, Cram H, et al. SMOF lipid in intestinal failure associated liver disease: experience in a regional centre. Paper presented at: British Society of Paediatric Gastroenterology, Hepatology and Nutrition Winter Meeting; January 27-29, 2010; Liverpool, England.
• Tillman, EM, Helms RA. Omega-3 long chain polyunsaturated fatty acids for treatment of parenteral nutrition—associated liver disease: a review of the literature. J Pediatr Pharmacol Ther. 2011;16(1):31-38.
• Diamond IR, Pencharz PB, Feldman BM, Lin SC, Moore AM, Wales PW. Novel lipid-based approaches to pediatric intestinal failure—associated liver disease. Arch Pediatr Adolesc Med. 2012;166(5):473-478. doi: 10.1001/archpediatrics.2011.1896.
• Meisel JA, Le HD, de Meijer VE, et al. Comparison of 5 intravenous lipid emulsions and their effects on hepatic steatosis in a murine model. J Pediatr Surg. 2011;46(4):666-673. doi: 10.1016/j.jpedsurg.2010.08.018.
• Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oil based emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics. 2008;121(3):e678-e686. doi: 10.1542/peds.2007-2248.
• Cheung HM, Lam HS, Tam YH, Lee KH, Ng PC. Rescue treatment of infants with intestinal failure and parenteral nutrition-associated cholestasis (PNAC) using parenteral fish-oil based lipid. Clin Nutr. 2009;28(2):209-212. doi: 10.1016/j.clnu.2009.02.004.
• Ekema G, Falchetti D, Boroni G, et al. Reversal of severe parenteral nutrition-associated liver disease in an infant with short bowel syndrome using parenteral fish oil (omega-3 fatty acids). J Pediatr Surg. 2008;43(6):1191-1195. doi: 10.1016/j.jpedsurg.2008.01.005.
• Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition-associated liver injury. Ann Surg. 2009;250(3):395-402. doi: 10.1097/SLA.0b013e3181b36657.
• Calkins KL, Dunn JC, Shew SB, et al. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr. 2014;38(6):682-692. doi: 10.1177/0148607113495416.
• Premkumar MH, Carter BA, Hawthorne KM, King K, Abrams SA. High rates of resolution of cholestasis in parenteral nutrition-associated liver disease with fish oil-based lipid emulsion monotherapy. J Pediatr. 2013;162(4):793-798.e1. doi: 10.1016/j.jpeds.2012.10.019.
• La Scala GC, Le Coultre C, Roche BG, Bugmann P, Belli DC. The addition of lipids increases the total parenteral nutrition-associated cholestasis in the rat. Eur J Pediatr Surg. 1993;3(4):224-227.
• Allardyce DB. Cholestasis caused by lipid emulsions. Surg Gynecol Obstet. 1982;154(5):641-647.
• Colomb V, Jobert-Giraud A, Lacaille F, Goulet O, Fournet JC, Ricour C. Role of lipid emulsions in cholestasis associated with long-term parenteral nutrition in children. JPEN J Parenter Enteral Nutr. 2000;24(6):345-350.
• Cober MP, Killu G, Brattain A, Welch KB, Kunisaki SM, Teitelbaum DH. Intravenous fat emulsion reduction for patients with parenteral nutrition—associated liver disease. J Pediatr. 2012;160(3):421-427. doi: 10.1016/j.jpeds.2011.08.047.
• Rollins MD, Ward RM, Jackson WD, et al. Effect of decreased parenteral soybean lipid emulsion on hepatic function in infants at risk for parenteral nutrition-associated liver disease: a pilot study. J Pediatr Surg. 2013;48(6):1348-1356. doi: 10.1016/j.jpedsurg.2013.03.040.
• Sanchez SE, Braun LP, Mercer LD, Sherrill M, Stevens J, Javid PJ. The effect of lipid restriction on the prevention of parenteral nutrition-associated cholestasis in surgical infants. J Pediatr Surg. 2013;48(3):573-578. doi: 10.1016/j.jpedsurg.2012.08.016.
• Nehra D, Fallon EM, Potemkin AK, et al. A comparison of 2 intravenous lipid emulsions: interim analysis of a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2014;38(6):693-701. doi: 10.1177/0148607113492549.
• Blackmer AB, Warschausky S, Siddiqui S, et al. Preliminary findings of long-term neurodevelopmental outcomes of infants treated with intravenous fat emulsion reduction for the management of parenteral nutrition-associated cholestasis. JPEN J Parenter Enteral Nutr. 2015;39(1):34-46. doi: 10.1177/0148607114551965.
• Wales PW, Allen N, Worthington P, George D, Compher C, Teitelbaum D; American Society for Parenteral and Enteral Nutrition. A.S.P.E.N. clinical guidelines: support of pediatric patients with intestinal failure at risk of parenteral nutrition-associated liver disease. JPEN J Parenter Enteral Nutr. 2014;38(5):538-557. doi: 10.1177/0148607114527772.
• Diamond IR, Grant RC, Feldman BM, et al. Expert beliefs regarding novel lipid-based approaches to pediatric intestinal failure—associated liver disease. JPEN J Parenter Enteral Nutr. 2014;38(6):702-710. doi: 10.1177/0148607113494213.