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American Academy of Pediatrics
Article

Randomized Trial of Very Low Birth Weight Infants Receiving Higher Rates of Infusion of Intravenous Fat Emulsions During the First Week of Life

Douglas Drenckpohl, Connie McConnell, Shirley Gaffney, Matt Niehaus and Kamlesh S. Macwan
Pediatrics October 2008, 122 (4) 743-751; DOI: https://doi.org/10.1542/peds.2007-2282
Douglas Drenckpohl
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Connie McConnell
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Shirley Gaffney
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Matt Niehaus
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Kamlesh S. Macwan
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Abstract

OBJECTIVE. The goal was to determine whether very low birth weight infants could tolerate higher rates of infusion of intravenous fat emulsion during the first week of life and maintain their serum triglyceride levels at ≤200 mg/dL.

METHODS. This was a randomized, controlled trial of 110 infants who were classified as appropriate for gestational age and had birth weights between 750 g and 1500 g. The primary clinical outcome was serum triglyceride levels; secondary outcomes also were monitored.

RESULTS. One hundred infants completed the study (experimental group: N = 48; control group: N = 52). Infants in the experimental group had significantly higher energy intake for the entire 7-day study period and achieved 90 kcal/kg per day (1 kcal = 4.184 kJ) significantly sooner (7.38 ± 3.381 days vs 9.44 ± 3.578 days). Triglyceride levels for infants in the experimental group remained significantly higher for the first 5 days of life. Fifteen percent of infants in the experimental group but only 4% of infants in the control group developed hypertriglyceridemia. Ten percent of infants in the control group but no infants in the experimental group required insulin therapy. Forty-two percent of infants in the experimental group and 17% of infants in the control group remained at ≥10th percentile for weight for age. Fourteen percent of infants in the control group but no infants in the experimental group developed necrotizing enterocolitis. Twenty-three percent of infants in the control group but only 6% of infants in the experimental group developed retinopathy of prematurity. There were no significant differences in other outcomes.

CONCLUSIONS. Very low birth weight infants can tolerate higher rates of infusion of intravenous fat emulsion solutions during the first week of life without significant adverse events.

  • intravenous fat emulsions
  • total nutrient admixtures
  • amino acids

Premature birth interrupts the natural growth period that occurs during the third trimester for the human fetus. The accretion of adipose tissue begins at gestational age of ∼25 weeks and continues at 1 to 3 g/kg per day.1 Very low birth weight (VLBW) infants have limited glycogen stores2 and adipose tissue because of their premature birth.

The immature gastrointestinal tract of VLBW infants can place them at risk for developing necrotizing enterocolitis (NEC).3 Premature infants are treated routinely with total parenteral nutrition (TPN), containing carbohydrates,4 amino acids,4 fat emulsions,4 vitamins,5 and minerals,5 to maintain their nutritional status during the first weeks of life. Traditionally, neonatologists began treatment with small amounts of macronutrients, such as amino acids at 0.5 g/kg per day and intravenous fat emulsion (IVFE) at 0.5 g/kg per day.6 These doses were chosen because it was thought that VLBW infants could not tolerate larger amounts of amino acids and that larger amounts of IVFE would put the infants at increased risk for developing hypertriglyceridemia.7

Recent research has focused on the effects of earlier administration of amino acids in TPN solutions for VLBW infants. Studies showed that provision of larger amounts of amino acids (1.5–3 g/kg per day) immediately after birth was safe and prevented losses of protein mass.8–10 The delivery of IVFE has not been as well studied as amino acid administration in TPN, because of the potential risk of intolerance7 and theoretical complications such as displacement of bilirubin,11 which would place the infant at risk for kernicterus11 and pulmonary dysfunction.12 Studies showed that providing premature infants with larger amounts of IVFE helped maintain their serum glucose levels after glucose infusion rates were decreased for the TPN solution.13–17 It was concluded that the glycerol present in IVFE solutions was used by the infant's gluconeogenesis pathway, allowing for continued glucose homeostasis.13–17 The goal of this study was to demonstrate that VLBW infants with birth weights of 750 to 1500 g would be able to tolerate a higher IVFE infusion rate within the first days of life (days 1–7), as evidenced by maintenance of serum triglyceride levels of ≤200 mg/dL. Secondary outcomes monitored were energy intake, time to regain birth weight, serum glucose levels, initiation of insulin therapy, anthropometric measurements, and clinical outcomes such as NEC, retinopathy of prematurity (ROP), chronic lung disease, intraventricular hemorrhage, patent ductus arterious, patent ductus arterious ligation, length of stay, and death.

METHODS

Experimental Design

This was a 16-month, randomized, nonblinded, controlled trial that took place from June 2005 through September 2006 at the 32-bed level III NICU at Children's Hospital of Illinois (Peoria, IL). The primary investigator and coinvestigators were responsible for recruiting all patients into this trial.

A total of 110 sealed envelopes were used to facilitate the randomization of this trial. Fifty-five sealed envelopes indicated that the infant would be assigned to the control group, and 55 sealed envelopes indicated that the infant would be assigned to the experimental group. The sealed envelopes were shuffled for 10 minutes and then given a study number of 1 through 110. After informed consent was obtained from a parent or guardian, a sealed envelope was opened, to reveal the study group in which the infant would be placed. The rationale for not blinding this study was that the NICU was experiencing a shortage of neonatologists to monitor the serum triglyceride levels and to adjust the IVFE, when they did not have a monthly rotation in the NICU.

The control group began treatment with 0.5 g/kg per day of 20% IVFE on the first day of TPN, and the experimental group began treatment with 2 g/kg per day of 20% IVFE on the first day of TPN. The IVFE level in the TPN was increased by 0.5 g/kg per day daily, until all infants in each group achieved 3 g/kg per day. The amino acid level in the TPN was started at 3 g/kg per day on the first day of TPN and was increased, as tolerated, by 0.5 g/kg per day, with a maximal intake of 3.5 g/kg per day. The initial dextrose concentration in the TPN was 10%, and the concentration was increased, as tolerated, to a final concentration of 12.5%. On the first day of life, fluid treatment was started at 70 mL/kg per day for all infants.

Serum triglyceride levels, along with other biochemical values, were measured daily for the first 7 days of TPN, through either the umbilical line or a heel stick. The serum triglyceride levels and other biochemical measurements were analyzed by the hospital's laboratory department. If hypertriglycemia occurred (≥201 mg/dL), then the IVFE concentration was decreased according to an approved algorithm (Table 1).

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TABLE 1

Algorithm for Adjusting IVFE in TPN Solution When Hypertriglycemia Occurs

Infants were weighed every other day and then daily when they surpassed 1500 g. They were weighed on an electronic scale by nursing personnel. Other anthropometric measurements (such as length and head circumference) were completed at admission and at discharge, by nursing personnel. Classification of newborns according to intrauterine growth and gestational age, as described by Lubchenco and colleagues,18,19 was used to define appropriate-for-gestational age (AGA) status for infants at admission to the NICU. The fetal growth chart for preterm infants20 was used to record the weight, length, and head circumference at discharge.

Study Population

Infants enrolled in this study had gestational ages between 26 and 32 weeks, had birth weights between 750 and 1500 g, and were classified as AGA on the basis of the approved growth chart. Singletons, twins, or triplets who met the weight and AGA status criteria were eligible to participate. Infants who were small for gestational age at birth, had serious congenital anomalies, and/or developed early sepsis were excluded from participation. The study was approved by the institutional review board for human subject research. Informed written consent was obtained from a parent of each infant, after the infant was admitted to the NICU and before TPN was initiated.

Total Parenteral Nutrition

All TPN solutions were prepared by the Parenteral and Enteral Nutrition Department at the Third Order of Saint Francis Saint Francis Medical Center, where the Children's Hospital of Illinois is located. Total nutrient admixture (TNA) solutions were used to deliver parenteral nutrients to each infant. The TNA solution was compounded from 70% dextrose (Baxter, Deerfield, IL), Trophamine (Braun, Irvine, CA), and 20% Intralipid emulsion (Baxter). The TNAs were prepared by using an Automix Plus compounder (Baxter), which blended the macronutrients together while the electrolytes, vitamins, minerals, cysteine (75 mg/kg per day), carnitine (25 mg/kg per day), and heparin (1 U/mL) were added manually. The TNA solution was administered through an umbilical artery catheter, umbilical venous catheter, peripherally inserted central catheter, or peripheral line. All TNA solutions, delivered either centrally or peripherally, included 1 U/mL heparin.

Data Collection and Outcome Variables

Data collection was completed by research nurses employed in the NICU. After the infants were enrolled, the research nurses collected the following information: demographic data, birth weight, gestational age at birth, serum triglyceride level, other nutritional laboratory values during the first 7 days of TPN, amount of IVFE in the TPN solution, fluid intake, initiation of insulin therapy, and day of regaining birth weight. The criterion to determine the day of regaining birth weight was that the infants must remain above their birth weight for 3 consecutive weights; then, the first day of the 3 weights was used as the date for regaining birth weight. A research nurse obtained clinical outcomes such as NEC, chronic lung disease, intraventricular hemorrhage (with grade), ROP (with stage), and death from the Vermont Oxford Network database. NEC was defined as the presence of pneumatosis intestinalis, verified with radiographs or during surgery. Chronic lung disease was defined as being dependent on oxygen at postmenstrual age of 36 weeks. Intraventricular hemorrhage was defined on the basis of ultrasound scans obtained before day 28 of life and was graded from 0 to 4 on the basis of the Vermont Oxford Network definitions. When a retinal examination was performed, results were graded from 0 to 4 on the basis of Vermont Oxford Network definitions. A registered dietitian calculated the total kilocalories per kilogram per day and recorded the day of life when the infants achieved a total energy intake of ≥90 kcal/kg per day (1 kcal = 4.184 kJ).

Statistical Analyses

The primary statistical analysis was to determine the effect of higher rates of infusion of 20% IVFE on serum triglyceride levels (≤200 mg/dL) during the first week of life. Sample size was calculated by using the method described by Browner et al21 for analytic studies and experiments. The effect of higher IVFE infusion rates on serum triglyceride levels was used as the basis for calculating the sample size, by using estimated data extrapolated from the study by Wilson et al22 of 125 VLBW infants and assuming an α value of .05 and power of .80. A sample size of 82 subjects (41 infants in each study group) was required to reach statistical significance of P < .05.

The secondary outcomes, such as days to achieve 90 kcal/kg per day, biochemical laboratory results, and amount of IVFE infused, and anthropometric results were evaluated by using independent, 2-sample, t tests. Levene's test was used to verify the homogenicity of the variances between the study groups. Demographic data, the number of infants of ≥10th percentile for weight for age at discharge, clinical outcomes, whether insulin therapy was initiated, and the number of infants who developed hypertriglyceridemia were evaluated with Pearson χ2 tests.

The means and SDs reported are for raw values. Because the triglyceride values and anthropometric values were positively skewed, Mann-Whitney U tests were performed to test for normality. All statistical tests were 2-tailed, and the level of significance was set at .05. All statistical analyses were performed by using SPSS 15.0 (SPSS, Chicago, IL). All data are expressed as mean ± SD.

RESULTS

Study Population

One hundred fifty-three infants were eligible to be enrolled in this study. Two parents refused to participate, and 41 infants began parenteral nutrition therapy before consent was obtained. Of the 110 infants who were assigned randomly in the study, 100 infants completed the study (Fig 1). Ten infants were withdrawn from the study because of exclusion criteria being met and/or deviations from the study protocol. Of the 100 infants who completed the study, 48 infants were in the experimental group and 52 infants were in the control group. There were no significant differences in race, gender, gestational age, or birth weight between the groups (Table 2).

FIGURE 1
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FIGURE 1

Diagram of enrollment. aindicates study protocol was not followed; triglycerides were not drawn; and TPN was prematurely stopped. bindicates 4 diagnosed with early sepsis; 2 study protocol was not followed; and 1 wrong birthweight was used.

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TABLE 2

Characteristics of Infants in the Study Groups

Total Parenteral Nutrition

On study day 1, when TPN was initiated, there was a significant difference between the 2 groups with respect to the amount of IVFE given (P < .001) (Table 3). The amount of IVFE given continued to be significantly different between the study groups on days 2 through 5 (P < .001). The amounts of IVFE present in the TPN solution were similar and not significantly different on study day 6 (P = .639) and study day 7 (P = .865).

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TABLE 3

Comparison of IVFE Levels in TPN

Energy

The energy intake per day in the experimental group remained statistically greater than that in the control group for all 7 days of the study period (Table 4). On study day 1, infants received 47.44 ± 12.27 kcal/kg per day, compared with 37.02 ± 8.95 kcal/kg per day in the control group (P < .0001). On study day 2, infants in the experimental group received 63.06 ± 10.83 kcal/kg per day, compared with 50.35 ± 7.04 kcal/kg per day in the control group (P < .0001). On study day 3, infants in the experimental group received 72.48 ± 9.90 kcal/kg per day, compared with 59.33 ± 7.40 kcal/kg per day in the control group (P < .0001). On study day 4, infants in the experimental group received 80.46 ± 12.60 kcal/kg per day, compared with 68.44 ± 7.62 kcal/kg per day in the control group (P < .0001). On study day 5, infants in the experimental group received 84.17 ± 8.73 kcal/kg per day, compared with 75.58 ± 8.55 kcal/kg per day in the control group (P < .0001). On study day 6, infants in the experimental group received 86.92 ± 9.54 kcal/kg per day, compared with 79.33 ± 11.62 kcal/kg per day in the control group (P < .001). On study day 7, infants in the experimental group received 88.38 ± 7.68 kcal/kg per day, compared with 84.22 ± 10.08 kcal/kg per day in the control group (P < .024). The experimental group achieved 90 kcal/kg per day significantly sooner, at an average of 7.38 ± 3.381 days, compared with 9.44 ± 3.578 days in the control group (P = .004).

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TABLE 4

Comparison of Daily Total Energy Intake

Biochemical Indicators of Nutritional Status

On study days 1 through 3, the serum triglyceride levels in the experimental group were significantly higher (P < .0001) than those in the control group (Table 5). On study day 4, serum triglyceride levels in the experimental group continued to be significantly higher (P = .001) than those in the control group. The variance in the serum triglyceride levels between the 2 study groups decreased from study day 5 through day 7, when the levels were not statistically significantly different (day 5: P = .324; day 6: P = .843; day 7: P = .838). Fifteen percent of infants in the experimental group had serum triglyceride levels of >200 mg/dL, whereas only 4% of infants in the control group had serum triglyceride levels of >200 mg/dL, which did not reach significance (P = .06).

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TABLE 5

Biochemical Indicators of Nutritional Status

Glucose Infusion Rates and Initiation of Insulin

On study days 1 through 3, the glucose infusion rates were not significantly different between the study groups (day 1: P = .828; day 2: P = .718; day 3: P = .382) (Table 6). On study days 4 through 6, the glucose infusion rates for infants in the experimental groups were significantly higher than those for infants in the control group (day 4: P = .001; day 5: P < .0001; day 6: P < .0001). On study day 7, the glucose infusion rates were similar between the groups and did not reach significance (P = .09). The average serum glucose levels were similar for the 2 groups throughout the study period, but 10% of infants in the control group had serum glucose levels of >200 mg/dL, requiring insulin therapy, whereas none of the infants in the experimental group required insulin, which was significant (P = .028).

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TABLE 6

Comparison of Glucose Infusion Rates and Initiation of Insulin Therapy

Weight and Anthropometric Measurements

Infants in the control group experienced 10% weight loss during the first week of life, whereas the experimental group experienced only an 8% weight loss, which was significant (P = .034) (Table 7). The time to regain birth weight was 12.86 ± 3.76 days in the control group and 12.5 ± 3.68 in the experimental group, which was not significant (P = .634). The weights, lengths, and head circumferences at discharge did not differ significantly between the study groups (weight: P = .675; length: P = .507; head circumference: P = .633). The proportions of infants in ≥10th percentile of weight for age at discharge were 17% in the control group and 42% in the experimental group, which was significant (P = .007). The postmenstrual age at discharge was 35.79 ± 4.17 weeks in the control group, compared with 35.0 ± 2.07 weeks in the experimental group, which did not achieve statistical significance (P = .267).

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TABLE 7

Comparison of Growth and Anthropometric Measurements

Clinical Outcomes

There were significant increases in the incidence rates of NEC and ROP in the control group (Table 8). Fourteen percent of infants in the control group developed NEC, whereas none of the infants in the experimental group developed NEC (P = .008). Twenty-three percent of infants in the control group were diagnosed as having ROP, compared with 6% in the experimental group (P = .019). None of the infants in either study group required surgical intervention for their ROP. There were no significant differences in the incidence rates of patent ductus arterious present (P = .896) or patent ductus arterious ligation (P = .142). Also, there were no significant differences between the study groups in the incidence rates of chronic lung disease and intraventricular hemorrhage (chronic lung disease: P = .413; intraventricular hemorrhage: P = .832). Six percent of infants in the control group died, whereas none in the experimental group died, which was not significant (P = .09).

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TABLE 8

Clinical Outcomes for Infants Receiving IVFE at Different Infusion Rates

DISCUSSION

The primary outcome of this study was to demonstrate that VLBW infants could tolerate higher rates of infusion of 20% IVFE during the first week of life, while maintaining serum triglyceride levels of ≤200 mg/dL. Infants in the experimental group had better energy intake, higher serum triglyceride levels, decreased initial weight loss, and better clinical outcomes, compared with infants in the control group. The benefit of providing additional energy from IVFE is that IVFE is a good concentrated source of energy. Twenty percent IVFE provides 2 cal/mL or 10 cal/g, compared with the amino acids in Trophamine (4 cal/g) or dextrose (only 3.4 cal/g). The composition of 20% Intralipid is 20 g of soybean oil per 100 mL, 1.2 g of egg yolk phospholipids per 100 mL, 2.25 g of glycerin per 100 mL, and water for injection. The 20 g of soybean oil per 100 mL contains 44% to 65% linoleic acid and 4% to 11% linolenic acids, which are essential fatty acids the human body cannot synthesize and requires as exogenous substrates to prevent deficiencies.

Fat, as an energy substrate, is used differently when the infant is in utero, compared with after birth. The concentrations of free fatty acids and ketone bodies in fetal circulation are very low, which indicates that lipid oxidation is diminished and lipids are a minor source of energy.23 The main source of energy for the fetus is glucose, with ∼70% of fetal glucose being converted to fat.23 When the infant is born, fat becomes the main source of energy, which is important for both metabolic fuels and fat deposition.23

Several studies with term neonates requiring TPN documented the positive effects of starting IVFE infusion at higher infusion rates. In a study conducted by Van Aerde et al,24 using indirect calorimetry, 28 AGA newborns were assigned randomly to 2 groups. The control group began treatment with TPN with dextrose and amino acids only. The infants assigned to the experimental group received TPN with dextrose, amino acids, and IVFE at 2 g/kg per day. The results of the study showed that infants in the experimental group had a significant reduction in energy expenditure, lower nonprotein carbon dioxide production, and lower nonprotein oxygen consumption.24 The control group had a significant excess of glucose utilization (overoxidation), which can be attributed to lipid synthesis from glucose. The control group had a higher rate of fat synthesis from excess glucose than did the experimental group, but the experimental group had a higher rate of fat storage than did the control group.24 The authors concluded that neonates would benefit from having IVFE replace a portion of the carbohydrate present in TPN because IVFE reduces gas exchange, resulting in less carbon dioxide production, which could be beneficial for infants with respiratory compromise. IVFE may also enhance lipid storage, which is an important component for growth in neonates.

In 1994, Van Aerde et al25 repeated the earlier study, using 20 AGA term infants. The infants were assigned randomly to 2 groups. The control group received only dextrose and amino acids in the TPN, whereas the experimental group received dextrose, amino acids, and IVFE at 2 g/kg per day in the TPN. Results from the later study showed that the experimental group had greater nitrogen retention and utilization than did the control group.25 The experimental group also demonstrated greater fat storage than did the control group, without increasing the energy expenditure from additional energy provided in the experimental group.25 The authors concluded that addition of a moderate amount of IVFE to dextrose-amino acid solutions in TPN would improve energy intake and enhance nitrogen retention, without influencing the contribution of fat and carbohydrate oxidation to the resting energy expenditure in term neonates.

Postnatal malnutrition and growth retardation within the first weeks of life can be a complication of prematurity.26 Embleton et al26 showed that, by the end of the first week of life, premature infants (gestational age of <34 weeks) have cumulative energy and protein deficits. Energy expenditure increases with postnatal age, for both nonventilated27,28 and ventilated29 premature infants, during the first weeks of life. It has been recommended that nonventilated premature infants should receive between 85 and 95 kcal/kg per day during the first week of life to achieve normal growth.30 In our study, we demonstrated that the infants in the experimental group had better energy intake during the entire study period than did infants in the control group, which resulted in achieving 90 kcal/kg per day significantly sooner, with less weight loss during the first week of life. Although the infants in the experimental group received more energy and had less initial weight loss, higher infusion rates did not seem to have an effect on the time it took for the study groups to regain or to exceed their birth weights.

There were no significant differences in anthropometric measures at discharge between the study groups, but infants in the experimental group were discharged an average 6.9 days earlier than infants in the control group. At discharge, more infants in the experimental group were at ≥10th percentile for weight for age, compared with infants in the control group. Premature infants with AGA status at birth can develop extrauterine growth restriction as a result of nutritional deficiencies during the first weeks of life.31,32 This growth restriction can persist during the infant's hospitalization33 and continue after discharge from the NICU.34 Growth restriction in premature infants can have long-term consequences, such as development of chronic diseases later in life, insulin resistance,35 obesity,36 and poorer developmental outcomes.37 A follow-up study is required to determine whether the long-term outcomes for the infants in the experimental group who remained at ≥10th percentile for weight for age after discharge would be different from those for infants in the control group.

The 2 improved clinical outcomes for the experimental group in this study were lower incidence rates of both NEC and ROP. Infants in the control group had a 14% incidence of NEC, whereas none of the infants in the experimental group developed NEC. The rate of NEC in the control group was also higher than the annual average our NICU has experienced over the past few years. The average annual incidence of NEC for infants <1500 g that we reported to the Vermont Oxford Network was between 2% and 8%. A study by Caplan et al,38 using newborn rats, showed that enteral formulas supplemented with long-chain polyunsaturated fatty acids reduced intestinal inflammation and decreased the incidence of NEC, compared with rats who received a nonsupplemented formula. A study by Carlson et al39 compared premature infants born at gestational age of ≤32 weeks who were fed either an enteral formula containing egg phospholipids or one without and examined the effects on clinical outcomes. Carlson et al39 showed that infants fed the phospholipid-containing formula had a lower incidence of NEC (P < .05), compared with infants in the nonsupplemented group. In a study by Ibrahim et al,40 32 ventilated premature infants, with birth weights of 501 to 1250 g and gestational ages at birth of 24 to 32 weeks, were assigned randomly to receive either early or late initiation of TPN. The early TPN group received 3.5 g/kg per day of amino acids (10% Trophamine) and 3 g/kg per day of 20% IVFE within 2 hours after birth, whereas the infants in the late TPN group received only dextrose for the first 48 hours of life and then began to receive 2 g/kg per day of amino acids and 0.5 g/kg per day of IVFE. The amino acid and IVFE levels were increased by 0.5 g/kg per day until a goal rate of 3.5 g/kg per day of amino acids and 3 g/kg per day of IVFE was achieved. The primary goal of the study was to investigate the effect of early initiation of TPN on the infant's nitrogen retention.40 The results from the study showed that infants in the early TPN group had positive nitrogen retention, as opposed to infants in the late TPN group, who did not (P < .05). Ibramin et al40 also showed that infants in the early TPN group had significantly lower blood glucose levels than did infants in the late TPN group. In our study, only infants from the control group required the initiation of insulin therapy to treat hyperglycemia, although infants in the control group had significantly lower glucose infusion rates on study days 4 through 6. The better control of serum glucose levels in the study by Ibrahim et al40 and our study may be attributed to the role that glycerol plays in IVFE. Glycerol can be used to produce glucose through the gluconeogenesis pathway and can maintain blood levels without the need for additional sources of dextrose in the TPN solution.13–16 Ibramin et al40 showed no significant difference in NEC or ROP rates, whereas our study did show significant differences in the incidences of NEC and ROP. These study differences may be attributable to the fact that infants in the study by Ibrahim et al40 had younger gestational ages and lower birth weights, compared with infants in our study. Infants in the study by Ibrahim et al40 had an average gestational age of 27 weeks at birth and an average birth weight of 900 g, whereas infants in our study had an average gestational age of 28 weeks at birth and an average birth weight of 1100 g.

There was a significant increase in the incidence of ROP in the control group, compared with the experimental group. Numerous studies showed the effect on visual acuity of infant formulas supplemented with long-chain polyunsaturated fatty acids, with varied conclusions.41–45 However, none of those studies was able to demonstrate that long-chain polyunsaturated fatty acids had a positive effect in reducing the incidence of ROP. In our study, premature infants in the experimental group received significantly more long-chain polyunsaturated fatty acids, which were present in the IVFE, during the first week of life. Often premature infants are not able to tolerate full enteral feedings supplemented with long-chain polyunsaturated fatty acids until ∼2 to 3 weeks of life, because of cautious feeding advancement. Because infants in the experimental group received additional sources of long-chain polyunsaturated fatty acids earlier, the fatty acids could be used for retina development, whereas infants in the control group did not receive significant amounts of IVFE until later in the week. It can be hypothesized from this study that earlier administration of IVFE may play a role in reducing the risk of ROP in premature infants. Additional studies are needed to confirm that increased IVFE infusion rates during the first week of life reduce the incidence of ROP in VLBW infants.

This study was limited in that, although it was randomized, it was not a double-blind trial. The research team did not include nitrogen balance studies or serum insulin levels in the study design to help determine what effects increased IVFE levels would have on these clinical values. Also, the maximal numerical value of what researchers consider lipid tolerance (serum triglyceride level of ≤200 mg/dL) was arbitrary determined on the basis of individualized institution standards. In the NICU at Children's Hospital of Illinois, premature infants are considered to be tolerating an infusion of IVFE if serum triglyceride levels are ≤200 mg/dL, but researchers have not determined what maximal numerical serum triglyceride value represents tolerance for premature infants. A study by Adamkin et al46 suggested that premature infants receiving continuous infusions of IVFE over a 20- to 24-hour period could tolerate serum triglyceride levels of <250 mg/dL without any undesirable consequences. Some NICUs consider lipid tolerance as having serum triglyceride levels of ≤150 mg/dL.

Infants in this study received TPN through TNA solutions, otherwise known as 3-in-1 solutions. This method of TPN administration is not the standard of care for the majority of NICUs in the United States. The advantages of TNA solutions are simple administration, less manipulation of the delivery system, reduced risk of contamination, and continuous administration of all nutrients.47 The main disadvantage of TNA solutions is that the addition of fat lipids increases the pH, which may decrease the solubility of calcium and phosphorus and increase the risk of precipitation.47 The addition of IVFE to TPN solutions also makes the solutions more opaque, which makes it more difficult for health care professionals to notice precipitation in the TPN solutions.47 For neonates, the problem of incompatibility of calcium and phosphate salts in TNA solutions is heightened because of amino acid concentrations, free calcium and phosphate ion concentrations, pH, and infusion temperature.48 In the NICU at Children's Hospital of Illinois, we order Trophamine to provide 3 g/kg per day of amino acids in the initial TPN solution. This amount of amino acids in the TPN solution decreases the pH and thereby reduces the risk for calcium phosphate precipitation. The pharmacy also uses calcium gluconate (instead of calcium chloride), which has increased solubility and decreases the risk for precipitation. All TNA solutions have a 1.2-μm, in-line filter in place as a safeguard, to prevent calcium phosphate precipitate from being infused into the patient. TNAs have been used for premature infants in the NICU at Children's Hospital of Illinois for >15 years, without any adverse events occurring.

CONCLUSIONS

Premature infants can tolerate higher IVFE infusion rates during the first week of life, without increased rates of adverse events. This study has shown that premature infants who receive larger amounts of IVFE during the first week of life had improved energy intake, had lower rates of NEC and ROP, and more often retained their AGA status at discharge. A larger, multicenter, randomized trial is needed to confirm the positive effects of higher IVFE infusion rates during the first week of life on clinical outcomes for premature infants. When initiating parenteral nutrition for premature infants on the first day of life, neonatal practitioners can safely use 2 g/kg per day of IVFE, to achieve better energy intake, with minimal risks to the premature infants.

Acknowledgments

This study was funded by a grant from the Children's Miracle Network (Peoria, IL).

Footnotes

    • Accepted January 7, 2008.
  • Address correspondence to Douglas Drenckpohl, MS, RD, CNSD, LDN, Neonatal Intensive Care Unit, Children's Hospital of Illinois, OSF St Francis Medical Center, Peoria, IL 61637. E-mail: douglas.c.drenckpohl{at}osfhealthcare.org
  • This trial has been registered at www.clinicaltrials.gov (identifier NCT00516997).

  • The authors have indicated they have no financial relationships relevant to this article to disclose.

  • What's Known on This Subject

    Traditionally, IVFEs have been introduced to premature infants at 0.5 to 1 g/kg per day at 1 to 3 days of life and increased cautiously, because of potential risks for intolerance such as hypertriglyceridemia, displacement of bilirubin, and pulmonary dysfunction.

    What This Study Adds

    This study showed that providing IVFE at 2 g/kg per day on the first day of life improved energy intake, decreased weight loss, allowed earlier regaining of birth weight, and decreased rates of NEC and ROP.

VLBW—very low birth weight • NEC—necrotizing enterocolitis • AGA—appropriate for gestational age • ROP—retinopathy of prematurity • IVFE—intravenous fat emulsion • TPN—total parenteral nutrition • TNA—total nutrient admixture

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Randomized Trial of Very Low Birth Weight Infants Receiving Higher Rates of Infusion of Intravenous Fat Emulsions During the First Week of Life
Douglas Drenckpohl, Connie McConnell, Shirley Gaffney, Matt Niehaus, Kamlesh S. Macwan
Pediatrics Oct 2008, 122 (4) 743-751; DOI: 10.1542/peds.2007-2282

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Randomized Trial of Very Low Birth Weight Infants Receiving Higher Rates of Infusion of Intravenous Fat Emulsions During the First Week of Life
Douglas Drenckpohl, Connie McConnell, Shirley Gaffney, Matt Niehaus, Kamlesh S. Macwan
Pediatrics Oct 2008, 122 (4) 743-751; DOI: 10.1542/peds.2007-2282
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