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

Pharmacy Times Health Systems Edition, July 2015, Volume 4, Issue 4

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

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


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.


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