Lipids in Parenteral Nutrition

After completing this article, readers should be able to: Early initiation of intravenous lipid administration is important because it increases energy intake through a small volume of parenteral fluid with low osmolality, provides essential fatty acids, and reduces carbon dioxide production relative to glucose as an energy substrate. The most widely available intravenous lipids are prepared from soybean oil or a combination of soybean and safflower oil. All of the emulsions are emulsified with egg yolk phospholipid, with glycerol added to achieve an isotonic solution (Table 1). Emulsions containing mixtures of olive and soybean oil and medium-chain triglycerides (MCTs) and soybean oil are also available. Infusion of intravenous lipid and parenteral nutrition in the same line may protect against phlebitis and loss of the intravenous vein, possibly due to physical coating of the vein with the lipid particles or the reduced osmolality of the infused solutions. The osmolality of intravenous lipid solutions, irrespective of the lipid concentration, is 268 mOsm/L, making them safe for both central and peripheral lines.The intravenous lipid particles have similar diameters to chylomicrons and acquire apo C11 from native lipoproteins after infusion. Clearance of intravenous lipid triglycerides proceeds by lipoprotein lipase, as described in Figure 1. However, dyslipoproteinemia, characterized by elevation of serum cholesterol and phospholipid secondary to infusion of 10% intravenous lipid emulsions, is well-known. This can occur even in the absence of elevated serum triglycerides and is largely the result of accumulation of abnormal particles containing phospholipid and cholesterol. These particles are generally known as lipoprotein (Lp) X. LpXs are formed from phospholipid present in the emulsion in excess of that needed to emulsify the triglyceride (mesophase phospholipid). These phospholipid particles acquire cholesterol, albumin, and apo E; are cleared by liver lipoprotein receptors and the reticuloendothelial system; and delay the clearance of infused triglycerides (Fig. 1). Intravenous lipids contain 12 g/L phospholipid, irrespective of triglyceride content. Infusion of 1 g triglyceride from a 10% emulsion results in concomitant infusion of 120 mg phospholipid, of which 40 mg is associated with triglycerides and 80 mg is present as liposomes. Infusion of 1 g triglyceride from a 20% emulsion results in infusion of 60 mg phospholipid associated with triglyceride and 20 mg phospholipid in liposomes. Plasma triglyceride levels and the accumulation of LpX are lower in preterm infants given 20% rather than 10% intravenous lipids. The 20% emulsions (2.0 kcal/mL) rather than 10% emulsions (1.1 kcal/mL) should be used for preterm infants because of the lower phospholipid load for a given calorie supply.The energy needs of the parenterally fed preterm infant are based on the energy expended to support basal metabolic rate, thermal losses, physical activity, and growth and are lower than those of enterally fed infants due to the loss of energy required for digestion and absorption of foods and fecal losses (Table 2). Clinical factors that affect energy requirements include fever, cardiac failure, major surgery, sepsis, intrauterine growth retardation, and bronchopulmonary dysplasia (BPD). Preterm infants generally require at least 70 kcal/kg per day of nonprotein energy, together with adequate protein to achieve growth and protein accretion. Parenterally fed preterm infants infused with dextrose or dextrose plus amino acids at 60 kcal/kg per day are unlikely to grow. Providing lipid in parenteral nutrition can avoid metabolic complications due to high glucose infusions. At an intake of nonprotein calories of 60 to 80 kcal/kg per day, glucose and fat provide similar protein-sparing. However, when energy needs are met, clinical factors are the predominant reason for selecting the proportion of energy as fat. Optimal nitrogen retention is found in newborns when 60% to 70% of the nonprotein energy is provided as carbohydrate and 30% to 40% is from fat.Concerns about intravenous lipid infusion have centered around morbidity and mortality associated with adverse effects on pulmonary functioning, possible increased risks of jaundice, and oxidant stress. Intravenous lipids could have adverse effects on pulmonary function for several reasons, including effects due to alteration of vascular tone that lead to pulmonary hypertension, increased membrane oxidant damage, or infiltration of pulmonary tissue by lipid particles. Early concerns focused on pulmonary fat accumulation when 10% emulsions were standard. Fat globules thought to be fat embolism in preterm infants infused with 10% emulsions subsequently were considered postmortem artifacts. Further, lipid accumulation also has been reported in pulmonary capillaries of infants who had not received lipid infusions.Information concerning intravenous lipid infusion and pulmonary function are conflicting. Some studies have suggested no difference in the rates of death, incidence of chronic lung disease, or in blood gases due to early rather than late initiation of intravenous lipid. However, a randomized study of 133 preterm infants that found no difference in overall mortality or chronic lung disease did document increased mortality and pulmonary hemorrhage among the subgroup of infants weighing 600 to 800 g who had been given intravenous lipid fewer than 12 hours after birth compared with infants not given lipid until day 7. Higher pulmonary arteriolar oxygen gradients also have been reported in preterm infants infused with 4 g/kg per day intravenous lipid over 16 hours (0.25 g/kg per hour) compared with those receiving 4 g/kg per day over 24 hours (0.166 g/kg per hour). Estimates of pulmonary vascular resistance derived from two-dimensional echocardiography have shown increased pulmonary arterial pressure with intravenous lipid infusion that was dose-dependent and increased by high infusion rates. The latter studies emphasize the importance of avoiding high rates of intravenous lipid administration.Fatty acids released by lipoprotein lipase hydrolysis of triglycerides are taken up by adipose tissue and muscle or released to the vascular system where they bind to albumin and are transported to the liver. Hydrolysis of intravenous triglyceride without fatty acid uptake has the potential to result in competition between unesterified fatty acids and bilirubin for binding sites on serum albumin, which would increase the risk for kernicterus. The displacement of bilirubin from albumin depends on the relative concentrations of albumin, bilirubin, and fatty acids. Accumulations of sufficiently high concentrations to result in clinical problems is unlikely, however, because free bilirubin is not generated until the molar ratio of free fatty acids to albumin exceeds 6. Ratios approaching this level are not found in clinical practice. No reports have indicated an increased incidence of kernicterus due to intravenous lipid infusion.Lipid emulsions contain large amounts of polyunsaturated fatty acids, which increase the susceptibility for peroxide formation. Lipid hydroperoxide concentrations vary among intravenous lipid batches and increase with light exposure, especially phototherapy light. There is a lower rate of lipid hydroperoxide formation for intravenous lipid emulsions prepared from olive and soybean oil mixtures, which contain lower amounts of polyunsaturated fatty acids, than from emulsions of only soybean oil. However, hydroperoxide also is formed in intravenous dextrose-amino acid solutions that contain multivitamins, which may be more important than the formation seen in intravenous lipids. Protecting intravenous lipids from light by covering bags and tubing with foil or using yellow or orange tubing reduces exposure of the infant to peroxidation products.Measurement of serum triglycerides is the preferred method for monitoring clearance of infused intravenous lipid. This automated enzyme-based biochemistry process requires a small amount of blood (10 mcL) and has a low intra- and interassay variation. Triglyceride concentrations up to 150 mg/dL (1.7 mmol/L) are acceptable; some intensive care units tolerate up to 200 mg/dL (2.3 mmol/L) before decreasing the lipid infusion. Accumulation of cholesterol-phospholipid particles can be monitored with a serum cholesterol assay. This automated biochemistry process similarly requires a small blood volume (10 mcL). An acceptable limit, based on the neonate enterally fed with human milk, is 160 mg/dL (4.2 mmol/L).The intake of n-6 fatty acids recommended by the American Academy of Pediatrics (1998) to prevent essential fatty acid deficiency in the enterally fed infant is 3% of total energy. At an energy intake of 120 kcal/kg per day, this is equivalent to 0.4 g (3.6 kcal) n-6 fatty acids. Infusion of 0.6 g/kg per day of soybean oil emulsion (66% linoleic acid) or 0.7 g/kg per day of a soybean-safflower oil emulsion (54% linoleic acid) provides this amount of n-6 fatty acids. The requirements for n-3 fatty acids are not fully resolved, but may be about 1% of energy. Infusion of 1.6 g/kg per day of soybean oil emulsion (8% linolenic acid) or 3.25 g/kg per day of a soybean-sufflower oil emulsion (4.2% linolenic acid) provides 1% energy of n-3 fatty acids at an energy intake of 120 kcal/kg per day.Even short delays in providing intravenous lipid to the parenterally fed preterm infant results in biochemical signs of essential fatty acid deficiency, characterized by an increase in the triene:tetraene ratio by 72 hours after birth. The abnormal fatty acid changes extend to the lung and probably other organs. Although the clinical implications of this change are not known, essential fatty acid deficiency does interfere with lung surfactant synthesis and normal platelet function. Biochemical and clinical signs of essential fatty acid deficiency can be avoided by infusing 0.5 to 1.0 g/kg per day of intravenous lipid. However, if the total energy intake is less than about 80 kcal/kg per day, linoleic acid and linolenic acid are likely to be oxidized to provide energy for essential metabolic and physiologic functions, and the limited tissue n-6 and n-3 fatty acid reserves will be mobilized.The duration of parenteral nutrition with inadequate energy for anabolic metabolism is an important determinant of the extent of depletion of arachidonic acid (AA) and docosahexaenoic acid (DHA). Because it is crucially important to preserve anatomic and functional development of the central nervous system (CNS), intravenous lipid must be administered with sufficient energy to allow prompt resumption of postnatal growth. To achieve this, the infusion should be initiated in the first 24 hours of life at 0.5 g/kg per day, unless contraindicated by acute respiratory distress or other life-threatening event. The infusion should be increased gradually at 0.25 to 0.5 g/kg per day to 3 g/kg per day (0.125 g/kg per hour), which is less than the maximum lipid clearance capacity in neonates of 0.3 g/kg per hour of triglyceride. Slower rates of advancement are more suitable for small infants who have limited adipose tissue mass. Serum triglycerides should be monitored and maintained under 150 mg/dL (1.7 mmol/L). Infants who have septicemia may have higher serum triglyceride and free fatty acid levels at a dose of 3 g/kg per day. Serum triglycerides should be monitored, and the dose reduced to 2 g/kg per day intravenous lipid or lower, if necessary, to maintain an acceptable serum triglyceride level until the septicemia is resolved. Lipid should be infused over 24 hours to maintain a low infusion rate. No benefit of cyclical/interrupted intravenous lipid infusion has been identified.Fat is the most variable macronutrient in human milk, ranging from about 2.5 to 5.0 g/dL, with a mean of 3.9 g/dL, and representing about 40% to 50% of total energy. Milk fat varies among women and markedly increases during a single lactation. Fatty acids used for the synthesis of milk triglycerides are derived from maternal plasma and from synthesis in the mammary gland. Following parturition, mammary cell lipogenic enzyme activity increases, irrespective of the length of gestation, and is increased further by nursing or milk expression. Saturated fatty acids synthesized in the mammary gland contain up to 14 carbons due the presence of thioesterase II, which terminates the elongation of fatty acids at 6 to 14 carbons. In all other tissues, thioesterase I terminates fatty acid synthesis at 16 carbons, ie, palmitic acid (16:0). Medium- and intermediate-chain length saturated fatty acids usually represent about 10% of human milk fatty acids (Table 3). This is increased by a high-carbohydrate/low-fat diet, which favors de novo fatty acid synthesis in the mammary gland. There appears to be little practically relevant difference in the milk fat content or composition between women delivering prematurely and at term.The mother’s diet has a major effect on the monounsaturated, polyunsaturated, and trans fatty acids in milk. Diets high in the monounsaturated fat (18:1) from olive or canola oils; linoleic acid (18:2n-6) from corn, safflower, sunflower, or soybean oil; or trans fatty acids from hydrogenated oils increase the milk 18:1, 18:2n-6, or trans fatty acids, respectively. The major dietary source of DHA is fatty fish. As for other unsaturated fatty acids, the mother’s intake of DHA is the single largest factor in determining the amount of DHA in milk. Human milk typically contains 34% 18:1, 12% to 14% 18:2n-6, 1.4% 18:3n-3, 0.4% 20:4n-6, and 0.2% 22:6n-3, although differences among individual women can be substantial.Milk expressed later in a single lactation (hindmilk) can have 1.5- to 2-fold higher fat than foremilk; concentrations of protein, important minerals, and water-soluble vitamins, on the other hand, are not different. If the mother produces sufficient volume, selective feeding of hindmilk can result in feedings of higher caloric density, on average providing about 10% more energy than a composite milk expression. This may be useful in facilitating greater weight gain in preterm infants whose growth rates are less than 15 g/kg per day. We have tested fractionation of milk by selectively collecting milk expressed after the first 2 minutes, the last 85% of the total volume expressed, or following change in the color based on visual appearance. In our experience, all methods allow collection of hindmilk containing about 1.5 g/dL higher fat content than in foremilk. Mothers, however, find it easiest to collect milk with a protocol based on time. Expression of a sufficient volume of milk to meet the needs of the fully enterally fed preterm infant is usually achieved with about six sessions of milk expression for a total of 120 minutes per day.Because human milk is not homogenized, the fat will separate on standing and may adhere to containers, feeding tubes, and syringes. Fat loss due to adherence to feeding systems is greatest with continuous feeding. Losses can be minimized by keeping tubing lengths short and orienting any syringes upright.Fortification of expressed human milk is widely considered the standard for feeding preterm infants. Human milk can be fortified using commercially available liquid or powdered human milk fortifiers. Commercial human milk fortifiers in North America are Similac Human Milk Fortifier® (powder) (Ross Products Division, Abbott Laboratories, Columbus, Ohio), Similac Natural Care Human Milk Fortifier® (liquid) (Ross Products Division, Abbott Laboratories), and Enfamil Human Milk Fortifier® (powder) (Mead Johnson Nutritionals, Evansville, Ind.) (Table 4). Addition of these fortifiers, modular fat (Table 5) and other macronutrient supplements, or powdered formulas intended for postterm infants alters the proportion of dietary energy from fat and sometimes the fat composition of the milk. Supplemental calcium may influence both calcium and fat absorption, depending on the calcium salt (due to the formation of insoluble soaps of calcium and fatty acids). For example, preterm infants fed expressed human milk fortified with a fortifier containing calcium gluconate and glycerophosphate had lower fat absorption than did infants fed preterm infant formula.Pasteurization reduces the absorption of human milk fat from 90% to 75%, possibly due to inactivation of bile salt-stimulated lipase, changes in the physical structure of the milk fat globule, and breakdown of triglyceride to fatty acids. Sterilization can reduce fat absorption by another 10%. Triglycerides may be broken down to free fatty acids in milk kept at room temperature or stored in a refrigerator. The release of saturated fatty acids from human milk has implications for both fat and calcium absorption.Preterm infant formulas typically contain 47% of total energy as fat. The fat is provided as a blend of 40% to 50% MCT oil with other vegetable oils (Table 6). MCTs are used as an alternate to the longer-chain saturated fat in term infant formulas. Some preterm formulas in Europe contain 20% of the fat as MCTs. Follow-up formulas for feeding preterm infants after hospital discharge contain 20% to 25% MCT blended with vegetable oils.MCT oil is prepared by distillation of coconut oil and contains 65% to 75% 8:0, 25% to 35% 10:0, and 1% to 3% of 6:0 and 12:0. The physical properties of triglycerides containing medium-chain fatty acids (MCFA) differ in several important ways from those containing long-chain fatty acids, and this has significance for pathways of fat absorption and metabolism (Fig. 2). Gastric hydrolysis of MCT can liberate 8:0, which can be absorbed directly through the gastric mucosa. Absorption of MCT from the small intestine also can proceed without intraluminal hydrolysis. These properties facilitate fat absorption in newborns, in whom pancreatic lipase enzyme activity and the bile salt pool are low, and in patients who have pancreatic or hepatobiliary insufficiency or a reduced intestinal length for fat digestion. Despite this, the evidence that MCT improves fat absorption in preterm infants is controversial. MCTs that are absorbed intact are hydrolyzed by mucosal lipase to liberate MCFA, which together with absorbed MCFA are transported directly to the liver bound to albumin. Subsequent beta-oxidation to CO2 and adenosine triphosphate occurs rapidly and independently of carnitine acyl transferases, which regulate the transfer of long-chain fatty acids into the mitochondria. The rapid beta-oxidation of MCFA leads to a rise in acetyl CoA in excess of metabolism in the tricarboxylic acid cycle. As a result, ketone bodies, which are formed by condensation of two acetyl CoA molecules, are formed. Some MCFA undergo ω-oxidation on the with formation of acids that are in the The elevation of acids is not sufficient to about adverse effects to the In the fed infant in energy should not be needed as an alternate to glucose to support energy The of MCTs rather than longer-chain saturated fatty acids has been reported to result in lower DHA in plasma lipids of preterm infants. However, MCTs may facilitate higher fat and calcium absorption than long-chain saturated fatty in essential fatty acids in infant nutrition has focused on the of DHA in and Early studies that the of linolenic acid to DHA may be in the and suggested that DHA may be a essential for infants. However, early studies reported lower growth among preterm infants fed formulas containing DHA from n-3 fatty acids can interfere with the metabolism of which is for the of n-6 fatty acids in normal growth. This in to the that formulas with DHA also should contain a source of and should the amounts and ratio of and DHA to in human milk in North of and DHA include egg and derived from or cell Triglycerides prepared from or the of containing 40% to 50% or the of only small amounts of the oil to the on the other hand, contain low amounts of and to be added at to 20% of the fat blend to achieve levels of in the The of egg lipids may be by oil or oil as a source of are the of these oils in infant formulas and the of that will be needed following for clinical studies that of with DHA may increase early visual and possibly other of development in small preterm infants. is not this effect has n-3 and n-6 fatty acids are and the for that platelet Because a risk of adverse infants or infant formulas should not be directly with or other commercially prepared should be used when they available.

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