- Email: [email protected]
Parenteral nutrient needs of very low birth weight infants
Parenteral nutrient needs of very low birth weight infants Richard J. Schanler, MD, Robert J. Shulman, MD, a n d Laurel L. Prestridge, MD From the U.S.Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center and the Sections of Neonatology and Pediatric Gastroenterology, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston
Objective: To determine nitrogen and mineral needs in parenterally nourished very low birth weight infants. Design: Prospective observational study. Setting: Neonatal intensive care unit. Patients: Twenty-four very low birth weight infants (<1.2 kg) e x p e c t e d to receive parenteral nutrition (PN) exclusively for 3 weeks beginning 3 days after birth. Interventions: Infants received PN solutions a c c o r d i n g to nursery protocol. Serial 24-hour b a l a n c e studies were c o n d u c t e d twice weekly. Clinical therapies were tabulated. Main outcome measures: Intake, urinary excretion, and a p p a r e n t retention of nitrogen, sodium, potassium, zinc, copper, calcium, phosphorus, and magnesium after initiation of PN. Results: Although urinary K, Zn, Ca, P, and Mg excretion (but not N, Na, and Cu excretion) increased after PN therapy was begun, net nutrient retention increased significantly a b o v e baseline for all nutrients. A v e r a g e w e e k l y nutrient retention was significantly b e l o w intrauterine estimates of nutrient accretion for N, Na, Ca, P, and Cu; closely a p p r o x i m a t e d estimates for Zn; and significantly e x c e e d e d those for K and Mg. Regression analysis was used to predict parenteral nutrient intakes that would support postnatal nutrient retentions e q u i v a l e n t to the intrauterine estimates. Postnatal therapy with d e x a m e t h a s o n e a f f e c t e d N, P, and K excretion and retention. Conclusions: Soon after PN administration is begun, positive nutrient b a l a n c e may be a c h i e v e d early in the neonatal period. The m a g n i t u d e of this effect remains uniform during PN administration. Adjustments in parenteral nutrient intake are n e e d e d to provide nutrient intakes sufficient to support postnatal retention at rates similar to those of intrauterine accretion. These data should be considered in the design of future studies to determine optimal PN needs of very low birth weight infants. (J PEDIATR1994;125:961-8)
Supported by the General Clinical Research Center, Baylor College of Medicine/Texas Children's Hospital Clinical Research Center (grant No. MO 1-RR-00188) National Institutes of Health. Funding provided from the U.S. Department of Agriculture/Agricultural Research Center, under cooperative agreement No. 586250-1-003. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does men-
tion of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Submitted for publication Jan. 31, 1994; accepted June 14, 1994. Reprint requests: Richard J. Schanler, MD, Children's Nutrition Research Center, 1100 Bates St., Houston, TX 77030. 9/23/58437
961
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Schanler, Shulman, and Prestridge
The parenteral nutrient needs of very low birth weight infants are not well defined, although these infants constitute the largest percentage of pediatric patients receiving parenteral nutrition. 1, 2 Estimates of needs often are cited from published data derived from older or enterally fed infants. 1 To compound the complexities of this issue, therapies common in the management of VLBW infants also may affect nutrient needs. Growth failure, for example, has been observed in VLBW infants who required prolonged pharmacologic doses of glucocorticoids postnatally. 3 To define more clearly the parenteral nutrient needs of VLBW infants, we measured serial nitrogen, sodium, potassium, zinc, copper, calcium, phosphorus, and magnesium balances (intake - urinary losses) during the course of PN therapy and compared the results with estimates of intrauterine nutrient accretion. METHODS Infants from the neonatal nurseries of Texas Children's Hospital who were appropriate in size for gestational age were recruited for study on the basis of the following criteria: birth weight less than 1.2 kg, no major congenital malformations, and the expectation that PN would be used for approximately 3 weeks. These infants were participants in a randomized, controlled, 4 double-blind study to evaluate the effects of different Ca and P concentrations in PN on Ca and P retention. 4 Informed written consent was obtained from parents, and the protocol was approved by the review boards for human research at our institutions. Infants were enrolled by the day after birth, The PN solutions differed only in their content (per liter) of calcium gluconate (12 vs 17 mmol, 480 vs 680 mg Ca) and potassium monobasic-dibasic phosphate (15 vs 20 mmol, 465 vs 620 mg P). The remaining nutrient concentrations (per liter) were similar: amino acids, 22 gm (TrophAmine [Kendall-McGaw], plus L-cysteine, 30 mg/gm amino acid); glucose, 125 gm; magnesium sulfate, 4 mmol (96 mg Mg); sodium chloride, 26 mmol (600 mg Na); and potassium (chloride or phosphate), 29 mmol (1130 mg K). Multivitamins (M.V.I. Pediatric [Rhone-Poulenc-Rorer], 2 m l . kg -~ 9 day -a) and trace elements were added daily. Trace element amounts (per kilogram per day) were as follows: zinc sulfate, 4.6 #mol (300 #g Zn); copper sulfate, 0.6 #mol (40 #g Cu); chromium chloride, 0.008 #mol (0.4 #g Cr); selenious acid, 0.025 #tool (2 #g Se); and manganese sulfate, 0.18 Fzmol (10 Fzg Mn). Adjustments in the Na and K content of the PN solutions were allowed as indicated clinically. Parenteral nutrition therapy was begun at the discretion of the attending neonatologist, generally on postnatal day 3, and the volume was increased in stepwise increments, by protocol, from days 3 to 6. Thereafter, fluid volumes were
The Journal of Pediatrics December 1994
adjusted daily on the basis of body weight to maintain a PN intake of 130 ml/kg. Intravenous administration of lipid emulsion (20% Intralipid; KabiVitrum Inc., Clayton, N.C.) was started on day 5, and quantities were increased daily from 1 to 4 gm/kg, as indicated, on the basis of whether serial serum triglyceride concentrations remained less than 1.7 mmol/L (150 mg/dl). Additional fluid needs, as indicated clinically, were met with parenterally administered glucose solutions. The study interval began with the first day of PN administration (approximately day 3 after birth) and ended when enteral feeding accounted for more than 15% of the infant's daily energy intake. Nutrient and energy intakes were computed daily during the interval. The N, Na, K, Zn, Cu, Ca, P, and Mg content was determined in all medications and fluids given during the balance studies and added to the computed intakes. Only the Na content of medications and additional fluids significantly augmented the intake of that nutrient. The incidence and duration of medical therapies and medication use were tabulated. A baseline 24-hour collection of urine and sample of 24I
PN VLBW
Parenteral nutrition Very low birth weight
I
hour intravenous fluid intake were obtained. After the start of PN therapy, twice-weekly urine samples were collected for 24 hours; on the same day, PN samples were obtained from the beginning and end of the respective 24-hour infusions. Urine was collected continuously for 24 hours as described previously.4 Concentrations of Na, K, Zn, and Cu in PN solutions and in urine were determined by atomic absorption spectrophotometry. Concentrations of Ca, P, and Mg in PN solutions and urine were determined by automatic analyzer techniques (COBAS FARA; Roche Diagnostic Systems, Montclair, N.J.). Total N concentration in PN solutions and urine was determined by Kjeldahl methods (Kjeltec automatic analyzer 1030; Tecator Inc., Herndon, Va.). Protein was calculated as 6.25 x total N. Because stool output is negligible during PN administration, apparent retention (balance) was calculated as the difference between intake and urinary excretion. After a full volume of PN was achieved, intake, urinary excretion, and computed apparent retention were unaffected by time, as tested by repeated-measures analysis of variance. The data in Figs. 1 to 6 are therefore grouped by weekly averages, and the average values during PN administration were used for comparison. Baseline measurements of intake, urinary excretion, and retention were compared with the respective average values during PN therapy by paired t test. Linear regression analyses were used to test the relationship between intake and excretion and between intake and
The Journal of Pediatrics Volume 125, Number 6, Part 1
Schanler, Shulman, and Prestridge
500. 400. 300.
963
[ ] Intake Urinary [ ] excretion 9 Net retention X•
' ~ 200. 100. s ;z;
O. -100.
-200
Prior to p N - - - 2 - ~ . 0.5
During PN 1.0 2.0 Postnatal age (wk)
3.0
Fig. t. Nitrogen intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 20 infants) and the average values each week (n = 20, 16, and 9 infants, respectively) during PN therapy in infants who have never received dexamethasone. Differences during PN therapy were not significant. Increases in intake (p <0.001) and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant.
[ ] Intake ~'o ~ lit
[ ] Urinary excretion 9 Net retention X-+SEM
i
"
9
9
4-
N
O-
r~O -2-41 IPri~ to P N ~ 0.5
I
During PN 1.0 2.0 Postnatal age (wk)
I 3.0
Fig. 2. Total sodium intake from all sources, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy9 Differences during PN therapy were not significant. Increases in intake (p <0.001) and net retention (p = 0.012} between baseline and the average weekly values computed during PN therapy were significant. (1 mmol Na = 23 mg.) retention 9 The effect of specific therapy on excretion and retention was tested by analysis of variance 9 Retention of nutrients during P N therapy were compared with estimated intrauterine accretion rates 5, 6 by means of a Student t test. The predicted nutrient intake that would support postnatal retention equivalent to the intrauterine accretion rate was determined from the linear regression analysis of intake and retention 9 Balance study data for Ca, P, and Mg have been reported previously 94 Analysis of covariance was used to account for the original group designation: standard versus
35% higher Ca and P concentrations 9 Where appropriate, data for Ca, P, and Mg are included for summary purposes9 Data are expressed as the mean ___ SD unless specified otherwise. RESULTS The study sample included 24 infants whose birth weight was 898 + 173 gm (range, 600 to 1115 gin}and gestational age 27 ___ 1.6 weeks (24 to 29 weeks). The P N infusion was begun at 3.4 + 0.9 days postnataUy (2 to 5 days after birth)
964
Schanler, Shulman, and Prestridge
3,5-
3-
,.=
2.52-
t~0 9
The Journal of Pediatrics December 1994
[ ] Intake Urinary [ ] excretion 9 Net retention X•
1.5-
O
o.5-
"5
0-
'5 -o.5-1-
During PN
-1.5 0.50
1.0 2.O Postnatal age (wk)
3.0
Fig. 3. Potassium intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 20) and the average values each week (n = 20, 16, and 9, respectively) during PN therapy in infants who have never received dexamethasone. Differences during PN therapy were not significant. Increases in intake (p <0.001), urinary excretion (p <0.001), and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant. (1 mmol K = 39 mg.)
~,
4
"~ 3 :~2
-1 0.5
1.o 2.o Postnatal age (wk)
3.0
Fig. 4. Zinc intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN administration were not significant. Increases in intake (p <0.001), urinary excretion (p <0.001), and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant. (1 /~mol Zn = 65 #g.) and continued for 21 _+ 6 days (10 to 35 days). The average total fluid and energy intakes during the study interval were 153 _+ 15 ml . kg -1 9 day -1 and 94 _+ 13 kcal 9 kg -1 9 day -1, respectively. The use and duration of specific therapies consistent with a group of moderately ill V L B W infants are shown in Table I. The original study group designation, standard versus 35% higher Ca and P concentrations in the P N solution, did not affect the results for other nutrients described below. Before P N infusion, the retention of N, Na, K, Zn, Cu,
and Mg (Figs. 1 to 6), and of Ca and P, was markedly negative. 4 Urinary losses of N, Na, and Cu were not affected by PN. Urinary excretion of K, Zn, Ca, P, and M g increased from baseline (p <0.01) but remained uniform each week during the P N interval. Significant increases in nutrient retention were observed for all nutrients after P N infusion was started. After complete P N was achieved, nutrient retention remained uniform throughout the study interval. We examined the relationships between intake and urinary excretion. Significant relationships (p <0.01) were
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Schanler, Shulman, and Prestridge
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[ ] Intake 0.8] [ ] Urinary excretion 9 0.6-
Net retention ~-*SEM
Ill
II
i
0.4-' 0 ::k
-~" 0.2O
~
0I Prior to PN i O i~
=i
During PN
I
I
0.5
I
1.0
2.0
3.0
P o s t n a t a l age (wk) Fig. 5. Copper intake, urinary excretion, and net retention (balance) before PN administration (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN therapy were not significant. Increases in intake (p <0.001) and in net retention (p <01001) between baseline and the average weekly values computed during PN therapy were significant. (1 t~mol Cu = 64/xg.)
0.8
0.6
[ ] Intake [ ] Urinary excretion 9 Net retention X-+SEM
0.4v
E
0.2-
cD ~1)
O-
-0.2 I
Prior to PN 0.5
During PN
I 1.0
2.0
3.0
P o s t n a t a l age ( w k ) Fig. 6. Magnesium intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN therapy were not significant. Increases in intake (p <0.001), urinary excretion (p
mechanical ventilation. U r i n a r y N and P excretion increased in infants receiving d e x a m e t h a s o n e c o m p a r e d with those not receiving the drug; values for N a n d P were as follows: 301 + 170 versus 155 + 63 m g N 9 kg - I 9 day -1 a n d l . 0 _+ 0.7vs0.4 + 0 . 3 m m o l P 9 kg -1 9 d a y - l ( 3 1 + 22 vs 12 + 9 m g P 9 kg -1 9 d a y - l ) , respectively (p <0.001). Significantly lower retentions of N (96 + 184 versus 247 +_ 6 7 m g 9 kg -1 , day - l [ p = 0.006]) and P (1. 3 --- 0.9 versus 1.6 + 0 . 4 m m o l 9 kg -~ 9 day -1 [40 _+ 2 8 v s 5 0 + 12 m g P . kg -1 9 d a y - l ; p = 0.04]) were observed in infants
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250- X+SEM
I 200
Table II. Relation between net retention (dependent variable) and intake (independent variable) for each nutrient
Nutrient "~ 100 . . . . . . . . . . . . . . . . . . . . . . . . .
o
Na
K
Zn
Cu
Ca
P
Mg
F i g . 7. Computed average N (n = 20), Na (n = 24), K (n = 20), Zn (n = 24), Cu (n = 24), Ca (n = 12), P (n = 10), and Mg (n = 24) retention during PN, expressed as a maximum percentage of the published intrauterine accretion rate. Infants included did not receive dexamethasone. For Ca and P, only the 35% higher calcium and phosphorus group from the original study 4 are included.
Table
I. Use and duration of specific neonatal therapies
Therapy Mechanical ventilation IPPB CPAP Oxygen Phototherapy Antibiotics Dexamethasone Dopamine Furosemide Indomethacin Morphine sulfate Phenobarbital
Intercept
1.0 0.65 0.80 0.82 0.94 0.87 0.85 0.65
-169 -3.7 -1.4 -0.8 -0.15 -0.01 -0.2 -0,13
0-497 mg 1.2-15.5 mmol 0-4.2 mmol 0-7.9 ~mol 0-1.0 tLmol 0-2.2 mmol 0-2.8 mmol 0-1.1 mmol
Predicted intake* (per kg 9 day-l) 494 mg 7.5 mmol 2.6 mmol 5.4 ~mol 1.0 #mol 3.0 mmol 2.8 mmol 0.4 mmol
,,H/,-,
50-
N
Slope
Intake range studied (per kg 9 d a y i)
n
Duration (days)
24 22 24 16 19 4 2 7 11 17 23
5-84 2-58 11-36 1-5 3-28 3-15 1-19 1-23 1-5 1-24 I-6
IPPB, Intermittent positive-pressure breathing; CPAP, continuous positive airway pressure.
who received dexamethasone than in those who did not, respectively. The magnitude of the difference in N excretion suggested that while receiving dexamethasone, infants lost protein at a rate of 1 g m 9 kg -1 9 day -1. Potassium excretion and retention were affected similarly (p <0.05). The duration of dexamethasone therapy negatively affected the net retention of N (p = 0.004) and K (p = 0.03). The median weight change during the balance studies also differed significantly between infants who received dexamethasone ( - 4 . 4 g m . kg - 1 . day -1) and those who did not (4.2 gm 9 kg -] 9 day -1) (p = 0.04). The sample size was too small, however, to detect differences, within infants, in excretion and retention before and after dexamethasone use. We compared our findings on nutrient retention with
N Na K Zn Cu Ca P Mg
All relationships significant at p <0.001. For conversion: 1 m m o l N a = 23 mg; 1 mmol K = 39 mg; 1 izmol Z n = 65 /zg; 1 izmol Cu = 64 pg; I m m o l Ca = 40 mg; 1 m m o l P = 31 rag; and 1 mmol M g = 24 nag. *Based on the relation between nutrient ~retention and intake, predicted intake is that derived f r o m the regression equation using the published intrauterine accretion value as the desired retention.
published intrauterine accretion rates. Figure 7 depicts the maximal percentage of the intrauterine accretion rate achieved for each nutrient measured in our study. The intrauterine accretion rate was closely approximated postnatally by the retention of Zn and exceeded by the retention of K and Mg. The retention of N, Na, and Cu was significantly below intrauterine accretion rates. The net retention of Ca and P, despite high Ca and P intake, also was significantly less than intrauterine accretion rates. The relation between net retention and intake for each nutrient was used to determine the predicted intake needed to meet the intrauterine accretion rate (Table II). Except for Ca, all predicted intakes were within the range studied. The predicted Ca intake, however, was above the limit studied; predicted P intake was at the upper limit studied; and Mg intake was near the lower limit studied. Because P N was administered at a rate of 130 ml 9 kg -I 9 day -1, the following concentrations (per liter) were predicted to meet intrauterine estimates: amino acids, 24 gm; Na, 58 mmol (1300 mg); K, 20 mmol (800 mg); Zn, 42 #mol (2.7 mg); Cu, 8 #mol (0.5 rag); Ca, 23 mmol (920 mg); P, 21 mmol (650 mg); and Mg, 3 mmol (72 mg). Because the N a content of medications and fluids affected the net intake, the predicted concentration included N a also administered via these routes. DISCUSSION When P N infusion was started in V L B W infants between 2 and 5 days after birth, we observed reversal of negative nutrient balances and marked increments in nutrient reten-
The Journal of Pediatrics Volume 125, Number 6, Part 1
tion. We observed that despite modest increases in urinary excretion for certain nutrients, parenteral nutrient intake was the major determinant of net retention. We also noted that therapy with dexamethasone affected nutrient excretion and retention. At the time of study, VLBW infants in our nursery were given PN routinely for several weeks before enteral nutrition was begun. Thus we were able to monitor these infants for a long period. Although we estimated parenteral nutrient needs for moderately ill VLBW infants, we did not study critically ill infants, such as those with ongoing nutrient losses from gastrointestinal disease or surgery. As indicated in other studies, those infant populations may require greater intakes of specific nutrients.7, 8 Early initiation of PN infusion appeared nutritionally beneficial and without risk for VLBW infants. The marked increase in N balance, after PN therapy was started in our study, corroborated published observations of increased protein synthesis in VLBW infants after the administration of essential amino acids in the first 3 days after birth. 9 Our data indicate that therapies employed in the management of VLBW infants may affect nutrient excretion and retention. Dexamethasone exerted the most striking effects on nutrient balance: N, P, and K retention were affected adversely. Although adverse effects on N balance in preterm infants receiving dexamethasone have been reported,10.11 data for other nutrients have not been provided. In addition, we observed the effects on N balance while VLBW infants received a broad range of dexamethasone dosages. Our data regarding increased urinary P losses support the occurrence of an overall catabolic process during dexamethasone therapy. The effects of dexamethasone on N, K, and P balances suggest an effect on skeletal muscle more than on bone. 3 These data warrant further investigations o f body composition changes in VLBW infants receiving dexamethasone. It may be appropriate to provide additional protein and P to VLBW infants during prolonged therapy with dexamethasone. The net retentions of N, Na, Cu, Ca, and P were significantly lower than, Zn was similar to, and both K and Mg exceeded intrauterine estimates. 5, 6 These comparisons were made after adjustments that excluded infants who received dexamethasone. For Ca and P comparisons in Fig. 7, only the group with 35% higher Ca and P was used. Therefore the comparisons are conservative. From the positive relation between intake and net retention, we derived a predicted nutrient intake that should result in net retention similar to that reported in utero. In comparison with the actual range of intakes studied, our data predicted a need for moderately increased N and Cu and decreased Mg content in future PN solutions. Ca and
Schanler, Shulman, and Prestridge
967
P intake, however, needs to be augmented significantly. This concern was addressed by our group previously.4 Our predictions for nutrient intake assume that a significant relation exists between retention and intake. James and MacMahon 12reported parenteral mineral target intake in low birth weight infants similar to that for Cu and Mg in our study, but they did not observe a significant relation between retention and intake for all nutrients evaluated. In addition, their data differ somewhat from those of our study, possibly because they evaluated data on only four infants. Our predicted parenteral Zn need was similar to that reported by Lockitch et al. 13 When intake during a 2week interval was 400 # g . kg - 1 . day -1 (6.1 /~mol 9 kg -1 9 day-l), they observed uniform serum Zn concentrations that were not seen with lesser intakes. Their study also suggested that an intake of 40 ~ g . kg -1 9 day -1 (0.6 ~mol. kg -1 9 day -1) maintained serum Cu concentrations. Our data also suggested slightly lower intake for Zn but similar intake for Cu than those reported for older, ill preterm infants.7 Whether all predicted intake levels are possible, given the solubility issues, remains to be determined. Greater amino acid concentrations, with the addition of cysteine hydrochloride, would be beneficial in formulating the predicted mixture. Alternative sources of mineral salts also may be necessary. We conclude that when PN infusion is started within a few days of birth, the negative nutrient balance in VLBW infants is reversed. These data can be used to predict a parenteral nutrient intake that would support optimal nutrient use by VLBW infants. We thank Mary Thotathuchery, Charles Imo, Suman Vaidya, and Nitesh Mehta for laboratory assistance, the staff members of the Texas Children's Hospital Pharmacy and Neonatal Intensive Care Unit for research support, J. Kennard Fraley for database assistance, and E. O. Smith, PhD, for statistical advice. REFERENCES
1. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988;48:1324-42. 2. Heird WC, Kashyap S, Gomez MR. Parenteral alimentation of the neonate. Semin Perinatol 1991;15:493-502. 3. Williams AF, Jones M. Dexamethasone increases plasma amino acid concentrations in bronchopulmonary dysplasia. Arch Dis Child 1992;67:5-9. 4. Prestridge LL, Schanler RJ, Shulman RJ, Burns PA, Laine LL. Effect of parenteral calcium and phosphorus therapy on mineral retention and bone mineral content in very low birth weight infants. J PEDIATR1993;122:761-8. 5. WiddowsonEM. Importance of nutrition in development,with special reference to feeding low-birth-weightinfants. In: Sauls
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6. 7.
8.
9.
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HS, Bachhuber WL, Lewis LA, eds. Proceedings of the Second Ross Clinical Research Conference: Meeting Nutritional Goals for Low-Birth-Weight Infants. Columbus, Ohio: Ross Laboratories, 1982:4-11. Ziegler EE, O'Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. Zlotkin SH, Buchanan BE. Meeting zinc and copper intake requirements in the parenterally fed preterm and fullterm infant. J PEDtATR 1983;103:441-6. Shulman RJ. Zinc and copper balance studies in infants receiving total parenteral nutrition. Am J Clin Nutr 1989; 49:879-83. Rivera A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res 1993;33:106-11.
The Journal of Pediatrics December 1994
10. Brownlee KG, Ng PC, Henderson M J, Smith M, Green JH, Dear PRF. Catabolic effect of dexamethasone in the preterm baby. Arch Dis Child 1991;6:!-4. 11. Van Goudoever JB, Wattimena JDL, Carnielli VP, Sulkers E J, Degenhart H J, Sauer PJJ. Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia. J PEDIATR 1994;124:112-8. 12. James BE, MacMahon RA. Balance studies of nine elements during complete intravenous feeding of small premature infants. Aust Paediatr J 1976;12:154-62. 13. Lockitch G, Godolphin W, Pendray MR, Riddell D, Quigley G. Serum zinc, copper, retinol-binding protein, prealbumin, and ceruloplasmin concentrations in infants receiving intravenous zinc and copper supplementation. J PED~ATR 1983; 102:304-8.
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Objective: To determine nitrogen and mineral needs in parenterally nourished very low birth weight infants. Design: Prospective observational study. Setting: Neonatal intensive care unit. Patients: Twenty-four very low birth weight infants (<1.2 kg) e x p e c t e d to receive parenteral nutrition (PN) exclusively for 3 weeks beginning 3 days after birth. Interventions: Infants received PN solutions a c c o r d i n g to nursery protocol. Serial 24-hour b a l a n c e studies were c o n d u c t e d twice weekly. Clinical therapies were tabulated. Main outcome measures: Intake, urinary excretion, and a p p a r e n t retention of nitrogen, sodium, potassium, zinc, copper, calcium, phosphorus, and magnesium after initiation of PN. Results: Although urinary K, Zn, Ca, P, and Mg excretion (but not N, Na, and Cu excretion) increased after PN therapy was begun, net nutrient retention increased significantly a b o v e baseline for all nutrients. A v e r a g e w e e k l y nutrient retention was significantly b e l o w intrauterine estimates of nutrient accretion for N, Na, Ca, P, and Cu; closely a p p r o x i m a t e d estimates for Zn; and significantly e x c e e d e d those for K and Mg. Regression analysis was used to predict parenteral nutrient intakes that would support postnatal nutrient retentions e q u i v a l e n t to the intrauterine estimates. Postnatal therapy with d e x a m e t h a s o n e a f f e c t e d N, P, and K excretion and retention. Conclusions: Soon after PN administration is begun, positive nutrient b a l a n c e may be a c h i e v e d early in the neonatal period. The m a g n i t u d e of this effect remains uniform during PN administration. Adjustments in parenteral nutrient intake are n e e d e d to provide nutrient intakes sufficient to support postnatal retention at rates similar to those of intrauterine accretion. These data should be considered in the design of future studies to determine optimal PN needs of very low birth weight infants. (J PEDIATR1994;125:961-8)
Supported by the General Clinical Research Center, Baylor College of Medicine/Texas Children's Hospital Clinical Research Center (grant No. MO 1-RR-00188) National Institutes of Health. Funding provided from the U.S. Department of Agriculture/Agricultural Research Center, under cooperative agreement No. 586250-1-003. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does men-
tion of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Submitted for publication Jan. 31, 1994; accepted June 14, 1994. Reprint requests: Richard J. Schanler, MD, Children's Nutrition Research Center, 1100 Bates St., Houston, TX 77030. 9/23/58437
961
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The parenteral nutrient needs of very low birth weight infants are not well defined, although these infants constitute the largest percentage of pediatric patients receiving parenteral nutrition. 1, 2 Estimates of needs often are cited from published data derived from older or enterally fed infants. 1 To compound the complexities of this issue, therapies common in the management of VLBW infants also may affect nutrient needs. Growth failure, for example, has been observed in VLBW infants who required prolonged pharmacologic doses of glucocorticoids postnatally. 3 To define more clearly the parenteral nutrient needs of VLBW infants, we measured serial nitrogen, sodium, potassium, zinc, copper, calcium, phosphorus, and magnesium balances (intake - urinary losses) during the course of PN therapy and compared the results with estimates of intrauterine nutrient accretion. METHODS Infants from the neonatal nurseries of Texas Children's Hospital who were appropriate in size for gestational age were recruited for study on the basis of the following criteria: birth weight less than 1.2 kg, no major congenital malformations, and the expectation that PN would be used for approximately 3 weeks. These infants were participants in a randomized, controlled, 4 double-blind study to evaluate the effects of different Ca and P concentrations in PN on Ca and P retention. 4 Informed written consent was obtained from parents, and the protocol was approved by the review boards for human research at our institutions. Infants were enrolled by the day after birth, The PN solutions differed only in their content (per liter) of calcium gluconate (12 vs 17 mmol, 480 vs 680 mg Ca) and potassium monobasic-dibasic phosphate (15 vs 20 mmol, 465 vs 620 mg P). The remaining nutrient concentrations (per liter) were similar: amino acids, 22 gm (TrophAmine [Kendall-McGaw], plus L-cysteine, 30 mg/gm amino acid); glucose, 125 gm; magnesium sulfate, 4 mmol (96 mg Mg); sodium chloride, 26 mmol (600 mg Na); and potassium (chloride or phosphate), 29 mmol (1130 mg K). Multivitamins (M.V.I. Pediatric [Rhone-Poulenc-Rorer], 2 m l . kg -~ 9 day -a) and trace elements were added daily. Trace element amounts (per kilogram per day) were as follows: zinc sulfate, 4.6 #mol (300 #g Zn); copper sulfate, 0.6 #mol (40 #g Cu); chromium chloride, 0.008 #mol (0.4 #g Cr); selenious acid, 0.025 #tool (2 #g Se); and manganese sulfate, 0.18 Fzmol (10 Fzg Mn). Adjustments in the Na and K content of the PN solutions were allowed as indicated clinically. Parenteral nutrition therapy was begun at the discretion of the attending neonatologist, generally on postnatal day 3, and the volume was increased in stepwise increments, by protocol, from days 3 to 6. Thereafter, fluid volumes were
The Journal of Pediatrics December 1994
adjusted daily on the basis of body weight to maintain a PN intake of 130 ml/kg. Intravenous administration of lipid emulsion (20% Intralipid; KabiVitrum Inc., Clayton, N.C.) was started on day 5, and quantities were increased daily from 1 to 4 gm/kg, as indicated, on the basis of whether serial serum triglyceride concentrations remained less than 1.7 mmol/L (150 mg/dl). Additional fluid needs, as indicated clinically, were met with parenterally administered glucose solutions. The study interval began with the first day of PN administration (approximately day 3 after birth) and ended when enteral feeding accounted for more than 15% of the infant's daily energy intake. Nutrient and energy intakes were computed daily during the interval. The N, Na, K, Zn, Cu, Ca, P, and Mg content was determined in all medications and fluids given during the balance studies and added to the computed intakes. Only the Na content of medications and additional fluids significantly augmented the intake of that nutrient. The incidence and duration of medical therapies and medication use were tabulated. A baseline 24-hour collection of urine and sample of 24I
PN VLBW
Parenteral nutrition Very low birth weight
I
hour intravenous fluid intake were obtained. After the start of PN therapy, twice-weekly urine samples were collected for 24 hours; on the same day, PN samples were obtained from the beginning and end of the respective 24-hour infusions. Urine was collected continuously for 24 hours as described previously.4 Concentrations of Na, K, Zn, and Cu in PN solutions and in urine were determined by atomic absorption spectrophotometry. Concentrations of Ca, P, and Mg in PN solutions and urine were determined by automatic analyzer techniques (COBAS FARA; Roche Diagnostic Systems, Montclair, N.J.). Total N concentration in PN solutions and urine was determined by Kjeldahl methods (Kjeltec automatic analyzer 1030; Tecator Inc., Herndon, Va.). Protein was calculated as 6.25 x total N. Because stool output is negligible during PN administration, apparent retention (balance) was calculated as the difference between intake and urinary excretion. After a full volume of PN was achieved, intake, urinary excretion, and computed apparent retention were unaffected by time, as tested by repeated-measures analysis of variance. The data in Figs. 1 to 6 are therefore grouped by weekly averages, and the average values during PN administration were used for comparison. Baseline measurements of intake, urinary excretion, and retention were compared with the respective average values during PN therapy by paired t test. Linear regression analyses were used to test the relationship between intake and excretion and between intake and
The Journal of Pediatrics Volume 125, Number 6, Part 1
Schanler, Shulman, and Prestridge
500. 400. 300.
963
[ ] Intake Urinary [ ] excretion 9 Net retention X•
' ~ 200. 100. s ;z;
O. -100.
-200
Prior to p N - - - 2 - ~ . 0.5
During PN 1.0 2.0 Postnatal age (wk)
3.0
Fig. t. Nitrogen intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 20 infants) and the average values each week (n = 20, 16, and 9 infants, respectively) during PN therapy in infants who have never received dexamethasone. Differences during PN therapy were not significant. Increases in intake (p <0.001) and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant.
[ ] Intake ~'o ~ lit
[ ] Urinary excretion 9 Net retention X-+SEM
i
"
9
9
4-
N
O-
r~O -2-41 IPri~ to P N ~ 0.5
I
During PN 1.0 2.0 Postnatal age (wk)
I 3.0
Fig. 2. Total sodium intake from all sources, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy9 Differences during PN therapy were not significant. Increases in intake (p <0.001) and net retention (p = 0.012} between baseline and the average weekly values computed during PN therapy were significant. (1 mmol Na = 23 mg.) retention 9 The effect of specific therapy on excretion and retention was tested by analysis of variance 9 Retention of nutrients during P N therapy were compared with estimated intrauterine accretion rates 5, 6 by means of a Student t test. The predicted nutrient intake that would support postnatal retention equivalent to the intrauterine accretion rate was determined from the linear regression analysis of intake and retention 9 Balance study data for Ca, P, and Mg have been reported previously 94 Analysis of covariance was used to account for the original group designation: standard versus
35% higher Ca and P concentrations 9 Where appropriate, data for Ca, P, and Mg are included for summary purposes9 Data are expressed as the mean ___ SD unless specified otherwise. RESULTS The study sample included 24 infants whose birth weight was 898 + 173 gm (range, 600 to 1115 gin}and gestational age 27 ___ 1.6 weeks (24 to 29 weeks). The P N infusion was begun at 3.4 + 0.9 days postnataUy (2 to 5 days after birth)
964
Schanler, Shulman, and Prestridge
3,5-
3-
,.=
2.52-
t~0 9
The Journal of Pediatrics December 1994
[ ] Intake Urinary [ ] excretion 9 Net retention X•
1.5-
O
o.5-
"5
0-
'5 -o.5-1-
During PN
-1.5 0.50
1.0 2.O Postnatal age (wk)
3.0
Fig. 3. Potassium intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 20) and the average values each week (n = 20, 16, and 9, respectively) during PN therapy in infants who have never received dexamethasone. Differences during PN therapy were not significant. Increases in intake (p <0.001), urinary excretion (p <0.001), and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant. (1 mmol K = 39 mg.)
~,
4
"~ 3 :~2
-1 0.5
1.o 2.o Postnatal age (wk)
3.0
Fig. 4. Zinc intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN administration were not significant. Increases in intake (p <0.001), urinary excretion (p <0.001), and net retention (p <0.001) between baseline and the average weekly values computed during PN therapy were significant. (1 /~mol Zn = 65 #g.) and continued for 21 _+ 6 days (10 to 35 days). The average total fluid and energy intakes during the study interval were 153 _+ 15 ml . kg -1 9 day -1 and 94 _+ 13 kcal 9 kg -1 9 day -1, respectively. The use and duration of specific therapies consistent with a group of moderately ill V L B W infants are shown in Table I. The original study group designation, standard versus 35% higher Ca and P concentrations in the P N solution, did not affect the results for other nutrients described below. Before P N infusion, the retention of N, Na, K, Zn, Cu,
and Mg (Figs. 1 to 6), and of Ca and P, was markedly negative. 4 Urinary losses of N, Na, and Cu were not affected by PN. Urinary excretion of K, Zn, Ca, P, and M g increased from baseline (p <0.01) but remained uniform each week during the P N interval. Significant increases in nutrient retention were observed for all nutrients after P N infusion was started. After complete P N was achieved, nutrient retention remained uniform throughout the study interval. We examined the relationships between intake and urinary excretion. Significant relationships (p <0.01) were
The Journal of Pediatrics Volume 125, Number 6, Part 1
Schanler, Shulman, and Prestridge
965
[ ] Intake 0.8] [ ] Urinary excretion 9 0.6-
Net retention ~-*SEM
Ill
II
i
0.4-' 0 ::k
-~" 0.2O
~
0I Prior to PN i O i~
=i
During PN
I
I
0.5
I
1.0
2.0
3.0
P o s t n a t a l age (wk) Fig. 5. Copper intake, urinary excretion, and net retention (balance) before PN administration (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN therapy were not significant. Increases in intake (p <0.001) and in net retention (p <01001) between baseline and the average weekly values computed during PN therapy were significant. (1 t~mol Cu = 64/xg.)
0.8
0.6
[ ] Intake [ ] Urinary excretion 9 Net retention X-+SEM
0.4v
E
0.2-
cD ~1)
O-
-0.2 I
Prior to PN 0.5
During PN
I 1.0
2.0
3.0
P o s t n a t a l age ( w k ) Fig. 6. Magnesium intake, urinary excretion, and net retention (balance) before PN therapy (baseline, n = 24) and the average values each week (n = 24, 18, and 11, respectively) during PN therapy. Differences during PN therapy were not significant. Increases in intake (p <0.001), urinary excretion (p
mechanical ventilation. U r i n a r y N and P excretion increased in infants receiving d e x a m e t h a s o n e c o m p a r e d with those not receiving the drug; values for N a n d P were as follows: 301 + 170 versus 155 + 63 m g N 9 kg - I 9 day -1 a n d l . 0 _+ 0.7vs0.4 + 0 . 3 m m o l P 9 kg -1 9 d a y - l ( 3 1 + 22 vs 12 + 9 m g P 9 kg -1 9 d a y - l ) , respectively (p <0.001). Significantly lower retentions of N (96 + 184 versus 247 +_ 6 7 m g 9 kg -1 , day - l [ p = 0.006]) and P (1. 3 --- 0.9 versus 1.6 + 0 . 4 m m o l 9 kg -~ 9 day -1 [40 _+ 2 8 v s 5 0 + 12 m g P . kg -1 9 d a y - l ; p = 0.04]) were observed in infants
966
Schanler, Shulman, and Prestridge
The Journal of Pediatrics December 1994
250- X+SEM
I 200
Table II. Relation between net retention (dependent variable) and intake (independent variable) for each nutrient
Nutrient "~ 100 . . . . . . . . . . . . . . . . . . . . . . . . .
o
Na
K
Zn
Cu
Ca
P
Mg
F i g . 7. Computed average N (n = 20), Na (n = 24), K (n = 20), Zn (n = 24), Cu (n = 24), Ca (n = 12), P (n = 10), and Mg (n = 24) retention during PN, expressed as a maximum percentage of the published intrauterine accretion rate. Infants included did not receive dexamethasone. For Ca and P, only the 35% higher calcium and phosphorus group from the original study 4 are included.
Table
I. Use and duration of specific neonatal therapies
Therapy Mechanical ventilation IPPB CPAP Oxygen Phototherapy Antibiotics Dexamethasone Dopamine Furosemide Indomethacin Morphine sulfate Phenobarbital
Intercept
1.0 0.65 0.80 0.82 0.94 0.87 0.85 0.65
-169 -3.7 -1.4 -0.8 -0.15 -0.01 -0.2 -0,13
0-497 mg 1.2-15.5 mmol 0-4.2 mmol 0-7.9 ~mol 0-1.0 tLmol 0-2.2 mmol 0-2.8 mmol 0-1.1 mmol
Predicted intake* (per kg 9 day-l) 494 mg 7.5 mmol 2.6 mmol 5.4 ~mol 1.0 #mol 3.0 mmol 2.8 mmol 0.4 mmol
,,H/,-,
50-
N
Slope
Intake range studied (per kg 9 d a y i)
n
Duration (days)
24 22 24 16 19 4 2 7 11 17 23
5-84 2-58 11-36 1-5 3-28 3-15 1-19 1-23 1-5 1-24 I-6
IPPB, Intermittent positive-pressure breathing; CPAP, continuous positive airway pressure.
who received dexamethasone than in those who did not, respectively. The magnitude of the difference in N excretion suggested that while receiving dexamethasone, infants lost protein at a rate of 1 g m 9 kg -1 9 day -1. Potassium excretion and retention were affected similarly (p <0.05). The duration of dexamethasone therapy negatively affected the net retention of N (p = 0.004) and K (p = 0.03). The median weight change during the balance studies also differed significantly between infants who received dexamethasone ( - 4 . 4 g m . kg - 1 . day -1) and those who did not (4.2 gm 9 kg -] 9 day -1) (p = 0.04). The sample size was too small, however, to detect differences, within infants, in excretion and retention before and after dexamethasone use. We compared our findings on nutrient retention with
N Na K Zn Cu Ca P Mg
All relationships significant at p <0.001. For conversion: 1 m m o l N a = 23 mg; 1 mmol K = 39 mg; 1 izmol Z n = 65 /zg; 1 izmol Cu = 64 pg; I m m o l Ca = 40 mg; 1 m m o l P = 31 rag; and 1 mmol M g = 24 nag. *Based on the relation between nutrient ~retention and intake, predicted intake is that derived f r o m the regression equation using the published intrauterine accretion value as the desired retention.
published intrauterine accretion rates. Figure 7 depicts the maximal percentage of the intrauterine accretion rate achieved for each nutrient measured in our study. The intrauterine accretion rate was closely approximated postnatally by the retention of Zn and exceeded by the retention of K and Mg. The retention of N, Na, and Cu was significantly below intrauterine accretion rates. The net retention of Ca and P, despite high Ca and P intake, also was significantly less than intrauterine accretion rates. The relation between net retention and intake for each nutrient was used to determine the predicted intake needed to meet the intrauterine accretion rate (Table II). Except for Ca, all predicted intakes were within the range studied. The predicted Ca intake, however, was above the limit studied; predicted P intake was at the upper limit studied; and Mg intake was near the lower limit studied. Because P N was administered at a rate of 130 ml 9 kg -I 9 day -1, the following concentrations (per liter) were predicted to meet intrauterine estimates: amino acids, 24 gm; Na, 58 mmol (1300 mg); K, 20 mmol (800 mg); Zn, 42 #mol (2.7 mg); Cu, 8 #mol (0.5 rag); Ca, 23 mmol (920 mg); P, 21 mmol (650 mg); and Mg, 3 mmol (72 mg). Because the N a content of medications and fluids affected the net intake, the predicted concentration included N a also administered via these routes. DISCUSSION When P N infusion was started in V L B W infants between 2 and 5 days after birth, we observed reversal of negative nutrient balances and marked increments in nutrient reten-
The Journal of Pediatrics Volume 125, Number 6, Part 1
tion. We observed that despite modest increases in urinary excretion for certain nutrients, parenteral nutrient intake was the major determinant of net retention. We also noted that therapy with dexamethasone affected nutrient excretion and retention. At the time of study, VLBW infants in our nursery were given PN routinely for several weeks before enteral nutrition was begun. Thus we were able to monitor these infants for a long period. Although we estimated parenteral nutrient needs for moderately ill VLBW infants, we did not study critically ill infants, such as those with ongoing nutrient losses from gastrointestinal disease or surgery. As indicated in other studies, those infant populations may require greater intakes of specific nutrients.7, 8 Early initiation of PN infusion appeared nutritionally beneficial and without risk for VLBW infants. The marked increase in N balance, after PN therapy was started in our study, corroborated published observations of increased protein synthesis in VLBW infants after the administration of essential amino acids in the first 3 days after birth. 9 Our data indicate that therapies employed in the management of VLBW infants may affect nutrient excretion and retention. Dexamethasone exerted the most striking effects on nutrient balance: N, P, and K retention were affected adversely. Although adverse effects on N balance in preterm infants receiving dexamethasone have been reported,10.11 data for other nutrients have not been provided. In addition, we observed the effects on N balance while VLBW infants received a broad range of dexamethasone dosages. Our data regarding increased urinary P losses support the occurrence of an overall catabolic process during dexamethasone therapy. The effects of dexamethasone on N, K, and P balances suggest an effect on skeletal muscle more than on bone. 3 These data warrant further investigations o f body composition changes in VLBW infants receiving dexamethasone. It may be appropriate to provide additional protein and P to VLBW infants during prolonged therapy with dexamethasone. The net retentions of N, Na, Cu, Ca, and P were significantly lower than, Zn was similar to, and both K and Mg exceeded intrauterine estimates. 5, 6 These comparisons were made after adjustments that excluded infants who received dexamethasone. For Ca and P comparisons in Fig. 7, only the group with 35% higher Ca and P was used. Therefore the comparisons are conservative. From the positive relation between intake and net retention, we derived a predicted nutrient intake that should result in net retention similar to that reported in utero. In comparison with the actual range of intakes studied, our data predicted a need for moderately increased N and Cu and decreased Mg content in future PN solutions. Ca and
Schanler, Shulman, and Prestridge
967
P intake, however, needs to be augmented significantly. This concern was addressed by our group previously.4 Our predictions for nutrient intake assume that a significant relation exists between retention and intake. James and MacMahon 12reported parenteral mineral target intake in low birth weight infants similar to that for Cu and Mg in our study, but they did not observe a significant relation between retention and intake for all nutrients evaluated. In addition, their data differ somewhat from those of our study, possibly because they evaluated data on only four infants. Our predicted parenteral Zn need was similar to that reported by Lockitch et al. 13 When intake during a 2week interval was 400 # g . kg - 1 . day -1 (6.1 /~mol 9 kg -1 9 day-l), they observed uniform serum Zn concentrations that were not seen with lesser intakes. Their study also suggested that an intake of 40 ~ g . kg -1 9 day -1 (0.6 ~mol. kg -1 9 day -1) maintained serum Cu concentrations. Our data also suggested slightly lower intake for Zn but similar intake for Cu than those reported for older, ill preterm infants.7 Whether all predicted intake levels are possible, given the solubility issues, remains to be determined. Greater amino acid concentrations, with the addition of cysteine hydrochloride, would be beneficial in formulating the predicted mixture. Alternative sources of mineral salts also may be necessary. We conclude that when PN infusion is started within a few days of birth, the negative nutrient balance in VLBW infants is reversed. These data can be used to predict a parenteral nutrient intake that would support optimal nutrient use by VLBW infants. We thank Mary Thotathuchery, Charles Imo, Suman Vaidya, and Nitesh Mehta for laboratory assistance, the staff members of the Texas Children's Hospital Pharmacy and Neonatal Intensive Care Unit for research support, J. Kennard Fraley for database assistance, and E. O. Smith, PhD, for statistical advice. REFERENCES
1. Greene HL, Hambidge KM, Schanler R, Tsang RC. Guidelines for the use of vitamins, trace elements, calcium, magnesium, and phosphorus in infants and children receiving total parenteral nutrition: report of the Subcommittee on Pediatric Parenteral Nutrient Requirements from the Committee on Clinical Practice Issues of the American Society for Clinical Nutrition. Am J Clin Nutr 1988;48:1324-42. 2. Heird WC, Kashyap S, Gomez MR. Parenteral alimentation of the neonate. Semin Perinatol 1991;15:493-502. 3. Williams AF, Jones M. Dexamethasone increases plasma amino acid concentrations in bronchopulmonary dysplasia. Arch Dis Child 1992;67:5-9. 4. Prestridge LL, Schanler RJ, Shulman RJ, Burns PA, Laine LL. Effect of parenteral calcium and phosphorus therapy on mineral retention and bone mineral content in very low birth weight infants. J PEDIATR1993;122:761-8. 5. WiddowsonEM. Importance of nutrition in development,with special reference to feeding low-birth-weightinfants. In: Sauls
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6. 7.
8.
9.
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HS, Bachhuber WL, Lewis LA, eds. Proceedings of the Second Ross Clinical Research Conference: Meeting Nutritional Goals for Low-Birth-Weight Infants. Columbus, Ohio: Ross Laboratories, 1982:4-11. Ziegler EE, O'Donnell AM, Nelson SE, Fomon SJ. Body composition of the reference fetus. Growth 1976;40:329-41. Zlotkin SH, Buchanan BE. Meeting zinc and copper intake requirements in the parenterally fed preterm and fullterm infant. J PEDtATR 1983;103:441-6. Shulman RJ. Zinc and copper balance studies in infants receiving total parenteral nutrition. Am J Clin Nutr 1989; 49:879-83. Rivera A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism of preterm infants during the first three days of life. Pediatr Res 1993;33:106-11.
The Journal of Pediatrics December 1994
10. Brownlee KG, Ng PC, Henderson M J, Smith M, Green JH, Dear PRF. Catabolic effect of dexamethasone in the preterm baby. Arch Dis Child 1991;6:!-4. 11. Van Goudoever JB, Wattimena JDL, Carnielli VP, Sulkers E J, Degenhart H J, Sauer PJJ. Effect of dexamethasone on protein metabolism in infants with bronchopulmonary dysplasia. J PEDIATR 1994;124:112-8. 12. James BE, MacMahon RA. Balance studies of nine elements during complete intravenous feeding of small premature infants. Aust Paediatr J 1976;12:154-62. 13. Lockitch G, Godolphin W, Pendray MR, Riddell D, Quigley G. Serum zinc, copper, retinol-binding protein, prealbumin, and ceruloplasmin concentrations in infants receiving intravenous zinc and copper supplementation. J PED~ATR 1983; 102:304-8.
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