PREVENTING CHOLESTASIS IN PREMATURE INFANTS USING SMOFLIPID

Background: Extreme low birth weight infants (ELBW, < 1000 gram birth weight) are typically dependent on parenteral nutrition (PN) for a prolonged period, putting them at risk for development of parenteral nutrition associated liver damage, namely parenteral nutrition associated cholestasis (PNAC) which - in severe cases - can progress to hepatic failure in up to 17 % in selected cohorts. Intravenous lipid emulsions (ILE) based on soy bean oil are standard of care in preterm infants. However, they have been implicated in the pathogenesis of PNAC. Fish oil is rich in omega-3-long chain polyunsaturated fatty acids that can be found accumulating in liver and brain during the last trimester of pregnancy. Omega-3-long chain polyunsaturated fatty acids are absent in soy bean oil. In pediatric patients, ILEs based on fish oil were proposed for therapy of established PNAC, supported by growing evidence. However, whether the development of PNAC can be primarily prevented in a high risk population such as ELBW infants is unknown. Furthermore there are currently no data on the long term effects of ILEs containing fish oil on neurodevelopment of ELBW infants. Aim: The proposed trial aims at prospectively investigating a fish oil containing ILE (SMOFlipid) for its protective effect against PNAC in ELBW infants compared to a soy bean based ILE (Intralipid). Study design: ELBW infants will be randomized to receive PN using either SMOFlipid or Intralipid. The primary outcome will be "PNAC" defined as an elevated conjugated bilirubin > 1.5 mg/dl measured on two consecutive occasions. The most important secondary outcome will be neurodevelopment at 12 and 24 months of corrected age. Outlook: The study is important, as a suspected role of fish oil containing ILEs for prevention of liver damage will be clarified conferring direct influence on clinical practice in care of ELBW infants. Furthermore follow up on neurodevelopment may form the basis for larger multi centre trials on the neurodevelopmental impact of ILE containing fish oil in ELBW infants.

Very premature infants need intravenous nutrition as long as milk feedings are not tolerated because of a still immature gastrointestinal tract. Normally, this process takes a few weeks. With ongoing intravenous nutrition, secretion of bile from the liver into the intestine is sometimes blocked which may damage the liver. It is common believe that this is due to the composition of intravenous feedings, namely fat emulsions based on exclusively soybean oil. A new fat emulsion for intravenous nutrition was recently developed that is composed of soybean oil, coco nut oil, olive oil and fish oil. This balanced mixture is rich in omega-3-fatty acids. It is believed that this could protect the liver while intravenous feedings are applied.In our study in 200 infants born below 1 kg, we have used either the standard soybean oil based fat or the balanced mixture that also contains fish oil. We found that infants who received the balanced mixture with fish oil showed fewer problems with bile flow. This result could however not be proven with statistical certainty (significance). Both fat emulsions were equal concerning the metabolic tolerance and growth of these infants. It is however of interest that those infants who received the mixed fat emulsion with fish oil showed an accelerated maturation of electric brain activity. It seems possible that omega-3-fatty acids in the fish oil caused this effect. Potentially these infants will also profit for their general neurological development later on. Follow-up of these infants over the first two years of life will help to clarify this question.