Reduction of Neonatal Parenteral Nutrition Associated Cholestasis Through Lipid Emulsions

NCT02633384 | Terminated Phase 4 DMC

• 1 other identifier: CHLC.CI70.2014
• Study Type: interventional
• Target: 52
• Locations: 0 countries
• Sites: N/A

Brief Summary

Parenteral nutrition associated cholestasis (PNAC) is a common complication of prolonged and exclusive parenteral nutrition (PN). Infants subjected to major surgery are often unable to receive enteral nutrition for a long period of time, during which they require exclusive PN. In preterm infants, hepatic immaturity is a predisposing factor. Intravenous lipid emulsions (ILE) used in PN may promote PNAC or protect against it depending on their composition. Medium chain triglycerides (MCT) may have a hepatic protective effect. Long chain triglycerides (LCT) of n-3 family may protect from PNAC. In several new-generation emulsions, the α-tocopherol content is higher than the gamma-tocopherol content, acting as an antioxidant, preventing lipid peroxidation. The incidence and severity of PNAC in term and near-term infants subjected to corrective surgery for congenital abnormalities and needing prolonged PN using the ILE SMOFlipid® or Lipofundin® is compared. The investigators hypothesise that SMOFlipid® is more protective from PNAC than Lipofundin®. Single-center, randomized, controlled and double-blinded trial on consecutive neonates admitted in the NICU, with gestational age of 34 weeks or over, undergoing corrective surgery of congenital anomaly of the digestive tract or indirectly affecting the digestive tract. Recruitment if PN with ILE was started within the first 48 hours after birth. Minimum intervention: exclusive PN for at least 1 week. Main outcome: incidence of cholestasis (conjugated serum bilirubin \>1 mg/dl \[34 mmol/L\]). Severity of cholestasis evaluated by the magnitude of the serum conjugated bilirubin and serum γ-glutamyltranspeptidase (GGT). Mixed effects regression models are used to take into account the correlation structure between measures in time. Crude and adjusted odds-ratios with corresponding 95% confidence intervals are calculated.

Conditions

Intrahepatic, Cholestasis

Keywords

Parenteral nutrition associated cholestasis; Intravenous lipid emulsions; Surgical neonates; Congenital gastrointestinal abnormalities

Outcome Measures

Primary Outcomes (1)

• Incidence of cholestasis

  Conjugated serum bilirubin \>1 mg/dl (34 mmol/L) (Moyer, 2004).

  From recruitment to full enteral feeding per mouth (up to 90 postnatal days)

Secondary Outcomes (1)

• Severity of cholestasis

  From recruitment to full enteral feeding per mouth (up to 90 postnatal days)

Study Arms (2)

SMOFlipid

EXPERIMENTAL

infants subjected to corrective surgery for congenital abnormalities and needing prolonged PN using a new generation intravenous lipid emulsion

Other: SMOFlipid

Lipofundin

OTHER

infants subjected to corrective surgery for congenital abnormalities and needing prolonged PN using a current intravenous lipid emulsion

Other: Lipofundin

Interventions

SMOFlipid OTHER

Exclusive total parenteral nutrition using a new generation intravenous lipid emulsion composed of 30% LCT n-6 (soybean oil), 30% MCT (coconut oil), 25% monounsaturated fatty acids (olive oil), 15% LCT n-3 (fish oil) and α-tocopherol

Also known as: SMOFlipid® (Fresenius Kabi)

SMOFlipid

Lipofundin OTHER

Exclusive total parenteral nutrition using a current intravenous lipid emulsion composed of 50% LCT (soybean oil) and 50% MCT (coconut oil)

Also known as: Lipofundin® (B Braun)

Lipofundin

Eligibility Criteria

• Age: 12 Hours - 48 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• neonates admitted in the NICU,
• gestational age of 34 weeks or over,
• undergoing corrective surgery of congenital anomaly of the digestive tract or indirectly affecting the digestive tract (eg, diaphragmatic hernia)
• initiation of PN with ILE within the first 48 hours after birth.

You may not qualify if:

• pre-natal or early neonatal (within the first 72 hours after birth) diagnoses of congenital or acquired hepato-biliary disease, such as biliary atresia, choledochal cyst, inborn errors of metabolism, intra-hepatic familial cholestasis, infectious hepatitis, neonatal idiopathic hepatitis, biliary lithiasis and abnormalities of liver function tests .
• later neonatal diagnoses of any above mentioned pathology.
• other congenital conditions affecting the liver function, such as meconium ileus associated with cystic fibrosis.
• treatment with ursodeoxycholic acid,
• interruption of PN for more than 48 hours for any reason, except for the postsurgical period after corrective surgery of the main condition,
• transference to another unit before completing 7 days of PN.

Sponsors & Collaborators

• Centro Hospitalar de Lisboa Central: lead

Related Publications (20)

• Burrin DG, Ng K, Stoll B, Saenz De Pipaon M. Impact of new-generation lipid emulsions on cellular mechanisms of parenteral nutrition-associated liver disease. Adv Nutr. 2014 Jan 1;5(1):82-91. doi: 10.3945/an.113.004796.

  PMID: 24425726 BACKGROUND

• Carter BA, Taylor OA, Prendergast DR, Zimmerman TL, Von Furstenberg R, Moore DD, Karpen SJ. Stigmasterol, a soy lipid-derived phytosterol, is an antagonist of the bile acid nuclear receptor FXR. Pediatr Res. 2007 Sep;62(3):301-6. doi: 10.1203/PDR.0b013e3181256492.

  PMID: 17622954 BACKGROUND

• Christensen RD, Henry E, Wiedmeier SE, Burnett J, Lambert DK. Identifying patients, on the first day of life, at high-risk of developing parenteral nutrition-associated liver disease. J Perinatol. 2007 May;27(5):284-90. doi: 10.1038/sj.jp.7211686. Epub 2007 Mar 8.

  PMID: 17344923 BACKGROUND

• Deckelbaum RJ. Intravenous lipid emulsions in pediatrics: time for a change? J Pediatr Gastroenterol Nutr. 2003 Aug;37(2):112-4. doi: 10.1097/00005176-200308000-00004. No abstract available.

  PMID: 12883292 BACKGROUND

• Driscoll DF, Bistrian BR, Demmelmair H, Koletzko B. Pharmaceutical and clinical aspects of parenteral lipid emulsions in neonatology. Clin Nutr. 2008 Aug;27(4):497-503. doi: 10.1016/j.clnu.2008.05.003. Epub 2008 Jun 26. No abstract available.

  PMID: 18582994 BACKGROUND

• Ekema G, Falchetti D, Boroni G, Tanca AR, Altana C, Righetti L, Ridella M, Gambarotti M, Berchich L. 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 Jun;43(6):1191-5. doi: 10.1016/j.jpedsurg.2008.01.005.

  PMID: 18558205 BACKGROUND

• Furst P, Kuhn KS. Fish oil emulsions: what benefits can they bring? Clin Nutr. 2000 Feb;19(1):7-14. doi: 10.1054/clnu.1999.0072. No abstract available.

  PMID: 10700528 BACKGROUND

• Goulet O, Ruemmele F. Causes and management of intestinal failure in children. Gastroenterology. 2006 Feb;130(2 Suppl 1):S16-28. doi: 10.1053/j.gastro.2005.12.002.

  PMID: 16473066 BACKGROUND

• Kelly DA. Liver complications of pediatric parenteral nutrition--epidemiology. Nutrition. 1998 Jan;14(1):153-7. doi: 10.1016/s0899-9007(97)00232-3.

  PMID: 9437702 BACKGROUND

• Schwab F, Geffers C, Barwolff S, Ruden H, Gastmeier P. Reducing neonatal nosocomial bloodstream infections through participation in a national surveillance system. J Hosp Infect. 2007 Apr;65(4):319-25. doi: 10.1016/j.jhin.2006.12.020. Epub 2007 Mar 12.

  PMID: 17350730 BACKGROUND

• Teitelbaum DH, Tracy T. Parenteral nutrition-associated cholestasis. Semin Pediatr Surg. 2001 May;10(2):72-80. doi: 10.1053/spsu.2001.22386.

  PMID: 11329608 BACKGROUND

• 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 Mar;121(3):e678-86. doi: 10.1542/peds.2007-2248.

  PMID: 18310188 RESULT

• Kaufman SS. Prevention of parenteral nutrition-associated liver disease in children. Pediatr Transplant. 2002 Feb;6(1):37-42. doi: 10.1034/j.1399-3046.2002.1o061.x.

  PMID: 11906641 RESULT

• Koletzko B, Goulet O. Fish oil containing intravenous lipid emulsions in parenteral nutrition-associated cholestatic liver disease. Curr Opin Clin Nutr Metab Care. 2010 May;13(3):321-6. doi: 10.1097/MCO.0b013e3283385407.

  PMID: 20393276 RESULT

• Lee SI, Valim C, Johnston P, Le HD, Meisel J, Arsenault DA, Gura KM, Puder M. Impact of fish oil-based lipid emulsion on serum triglyceride, bilirubin, and albumin levels in children with parenteral nutrition-associated liver disease. Pediatr Res. 2009 Dec;66(6):698-703. doi: 10.1203/PDR.0b013e3181bbdf2b.

  PMID: 19687773 RESULT

• Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB, Heyman MB; North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004 Aug;39(2):115-28. doi: 10.1097/00005176-200408000-00001.

  PMID: 15269615 RESULT

• Pichler J, Simchowitz V, Macdonald S, Hill S. Comparison of liver function with two new/mixed intravenous lipid emulsions in children with intestinal failure. Eur J Clin Nutr. 2014 Oct;68(10):1161-7. doi: 10.1038/ejcn.2014.118. Epub 2014 Jun 25.

  PMID: 24961544 RESULT

• Seida JC, Mager DR, Hartling L, Vandermeer B, Turner JM. Parenteral omega-3 fatty acid lipid emulsions for children with intestinal failure and other conditions: a systematic review. JPEN J Parenter Enteral Nutr. 2013 Jan;37(1):44-55. doi: 10.1177/0148607112450300. Epub 2012 Jun 8.

  PMID: 22683686 RESULT

• Van Aerde JE, Duerksen DR, Gramlich L, Meddings JB, Chan G, Thomson AB, Clandinin MT. Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets. Pediatr Res. 1999 Feb;45(2):202-8. doi: 10.1203/00006450-199902000-00008.

  PMID: 10022591 RESULT

• Pereira-da-Silva L, Nobrega S, Rosa ML, Alves M, Pita A, Virella D, Papoila AL, Serelha M, Cordeiro-Ferreira G, Koletzko B. Parenteral nutrition-associated cholestasis and triglyceridemia in surgical term and near-term neonates: A pilot randomized controlled trial of two mixed intravenous lipid emulsions. Clin Nutr ESPEN. 2017 Dec;22:7-12. doi: 10.1016/j.clnesp.2017.08.007. Epub 2017 Aug 26.

  PMID: 29415837 DERIVED

MeSH Terms

Conditions

Cholestasis, Intrahepatic

Interventions

SMOFlipid; Lipofundin

Condition Hierarchy (Ancestors)

Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases

Study Officials

• Luis Pereira-da-Silva, MD, PhD

  Neonatal Intensive Care Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: November 30, 2015
• First Posted: December 17, 2015
• Study Start: August 1, 2011
• Primary Completion: July 1, 2015
• Study Completion: April 1, 2017
• Last Updated: July 13, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will not share