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Camilia R. Martin, MD MS
Assistant Professor of Pediatrics, Harvard Medical School Associate Director, NICU, Department of Neonatology Director for Cross-Disciplinary Research Partnerships, Division of Translational Research Beth Israel Deaconess Medical Center, Boston MA IPOKRaTES Clinical Seminar January 26, 2013
Overview
2
Lipids
3
Early Nutritional & Postnatal Intestinal Development
4
Immunonutrients
Objectives
Review current recommendations for lipid delivery
Discuss fatty acid requirements during fetal development Demonstrate postnatal fatty acid alterations resulting from
current neonatal nutritional practices & its impact on health and disease Postulate potential strategies to optimize postnatal fatty acid levels
Lipid: Definition
Organic compound that is readily soluble in nonpolar
Lipids
Preterm infants have very limited endogenous lipid stores Essential component of parenteral nutrition Serves as a source of Linoleic Acid Necessary to prevent essential fatty acid deficiency (0.5 1.0
gm/k/day) Meets high energy needs: High caloric source at 9 kcal/gm Important source for gluconeogenesis; which, ultimately may also reduce need for increased glucose infusion rates Step-wise advancement starting at 1.0 gm/k/day to goal of 3.5 gm/k/day Monitor triglyceride levels 20% preparation recommended for neonates; improved tolerance over 10% solutions (decrease risk of hypertriglyceridemia, hypercholesterolemia, hyperphospholipidemia)
http://www.chemistryland.com/CHM151W/12-Final/triglyceride.jpg
http://faculty.uca.edu/johnc/phospholipid.jpg
(COOH)
Saturated: Saturated with hydrogens, every carbon links with the maximum number of hydrogens, thus all single bonds Unsaturated: Not every carbon links with the maximum number of hydrogens, thus some carbon-carbon links are double bonds
18:3 (n-3)
1 3
1. Total number of carbons (c) 2. Total number of double bonds 3. Number of carbon from the terminal methyl end with the first double bond
22:6 (n-3)
DHA
Inflammation
Nucleus
DHA and polyunsaturated fatty acids (PUFAs) are important in: 1. Maintaining the structure of the cell, and 2. Regulating the production of inflammatory proteins
1. 2. 3. 4. 5. 6. 7. 8.
Non-raft membrane Lipid raft Lipid raft associated transmembrane protein Non-raft membrane protein Glycosylation modifications (on glycoproteins and glycolipids) GPI-anchored protein Cholesterol Glycolipid http://en.wikipedia.org/wiki/File:Lipid_raft_organisation_scheme.svg
Biomagnification
Retinopathy of Prematurity: 40% Long-term cognitive impairment: 35% Chronic Lung Disease: 30-50%
Infection: 20%
Necrotizing Enterocolitis: 5%
What is common to many of these disease? 1. DHA is critical in brain and eye development 2. DHA prevents excessive inflammation
DHA No DHA
IV Fluids
Optimal Growth & Organ Development
1. What happens to DHA levels after premature birth? 2. If low, do they cause disease?
DHA No DHA
Proteins Sugars
IV Fluids
Fat
Optimal Nutrition
Median DHA levels in preterm infants rapidly decline, falling below levels discovered to be present throughout the 3rd trimester
8
Median DHA levels at birth in TERM infants
3 0
Martin et al, Journal of Pediatrics, 2011
Similarly, LA and AA levels rapidly change from blood levels discovered to be present throughout the third trimester
20 Linoleic Acid (LA) Median LA and AA levels, mol% 10 15
Median AA levels at birth in PRETERM infants Median AA levels at birth in TERM infants
5
0
Martin et al, Journal of Pediatrics, 2011
Low DHA Levels are Linked to the Development of Chronic Lung Disease (CLD)
7
Mean DHA levels for all infants
*
No CLD 5
+ CLD
3 0
(n=54)
1
(n=63)
2
(n=56)
3
(n=34)
4
(n=35)
Postnatal Alterations in Select Fatty Acids & Ratios are Associated with an Increased Risk of CLD & Late-Onset Sepsis
CLD LA AA DHA LA: DHA Late-onset sepsis LA AA DHA LA: DHA OR (95% CI) 0.9 (0.7, 1.1) 0.9 (0.6, 1.3) 2.5 (1.3, 5.0) 8.6 (1.4, 53.1) Hazard ratio (95% CI) 0.8 (0.7, 0.96) (1.3) 1.4 (1.1, 1.7) 1.4 (1.0, 2.0) 4.6 (1.5, 14.1) p 0.4 0.6 0.001 0.02 p 0.02 0.02 0.08 0.007
Models adjusted for gestational age, gender, growth restriction, severity of illness, total Intralipid intake Martin et al, Journal of Pediatrics, 2011
Postnatal Alterations in Select Fatty Acids Associated with an Increased Risk of CLD & Late-Onset Sepsis
DHA
CLD
Outcomes
Outcomes
AA
CLD
LOS
LOS
ROP 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
Odds Ratio
Odds Ratio
DHA Deficit
Parenteral phase
Enteral phase
Fats
Proteins
Carbohydrates
Postnatal DHA Deficiency Inevitable Consequence of Current Recommendations & Practice in Preterm Infants
Lapillonne 2010
Postnatal DHA Deficiency Inevitable Consequence of Current Recommendations & Practice in Preterm Infants
Lapillonne 2010
Early Alterations in Fatty Acids Occur During a Critical Period of Immune & Organ Development
Ileum
Lung
Ollero, et al. J Cellular Physiology 2004;200:235244
Microbiome
PPARs
Parenteral phase
Enteral phase
Parenteral phase
Enteral phase
AA+DHA
Egg PL
DHA
Control
21.5 / 9
13.7 / 5.7
Cochrane Neonatal Group. Publication status and date: 2011 Review content assessed as up-to-date: 27 December 2010 Schulzke SM, Patole SK, Simmer K. Longchain polyunsaturated fatty acid supplementation in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 2. Art. No.: CD000375. DOI: 10.1002/14651858.CD000375.pub4.Copyright 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
On pooling of results, no clear long-term benefits or harms (if growth the only parameter) were demonstrated for preterm infants receiving LCPUFA-supplemented formula.
DHA Deficit
Parenteral phase
Enteral phase
3 0
d14 d7
% infants
d5
d3 d0
23
24
25
26
27
1. 2. 3. 4.
Achieving Adequate Levels Targeting Critical Balance of n3:n6 Fatty Acids Ensuring Effective Digestion Optimizing Absorption
Unpublished data
Martin-Freedman Laboratory, Beth Israel Deaconess Medical Center
Lipid Emulsions
Deshpande and Simmer Current Opin in Clin Nutr and Met Care 2011
Omega-6 (linoleic)
Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Alwayn et al., Pediatr Res 2005;57:445-452.
Reversal of parenteral nutritionassociated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Gura KM et al., Pediatrics 2006;118(1):e197-201.
Omega-3 (linolenic)
Innis. NeoReviews. 2002;3(3):e49
2010 Patient population: n=40, BW< 1250g Intervention: Composition/blend of Omegaven & Clinoleic Control group: Historical - Clinoleic
Parenteral Nutrition of Preterm Infants with a Lipid Emulsion Containing 10% Fish Oil: Effect on Plasma Lipids and Long-Chain Polyunsaturated Fatty Acids
2011 Patient population: n=47, BW< 1250g Intervention: Omegaven vs IntraLipid N=23, 10% fish oil (2.3% DHA) v n=24 MCT/soybean oil (trace amounts DHA)
Conclusions
Lipids are an important source of energy and aids in gluconeogenesis
Goal: 3 3.5 g/kg/day
LCPUFAs are biomagnified from mother to fetus during the last trimester Fatty acids (FA) are essential for organ growth and regulation of
inflammation
FA profiles are dramatically altered in the early postnatal period Changes in postnatal FA profiles are linked to neonatal disease
New strategies, that include both the parenteral and enteral periods, need
THANK YOU
cmartin1@bidmc.harvard.edu