Effect of two amino acid solutions on leucine turnover in preterm infants

OBJECTIVE: To assess the effect of two different parenteral amino acid mixtures, Trophamine and Primene, on leucine turnover in preterm infants. METHOD: Leucine kinetics were measured with [5,5,5 D3]leucine tracer in 15 infants receiving Trophamine (group 'T') (mean birth weight 1,263 g) and 22 who received Primene (group 'P') (mean birth weight 1,336 g) during two study periods, within a few hours after birth but before introduction of parenteral amino acid solution, and again at postnatal day 7. The rate of appearance of leucine was calculated from the enrichment of alpha-ketoisocaproic acid in plasma. RESULTS: There were no significant differences in leucine turnover within a few hours after birth in the two groups. In the infants who received Primene leucine turnover on day 7 was significantly lower than in those who received Trophamine (269 +/- 43 vs. 335 +/- 27, p < 0.05). Despite a higher intake of leucine in the Trophamine group (108 +/- 10 vs. 77 +/- 8 micromol.kg(-1).h(-1)), leucine released from proteins at day 7 was higher in this group compared to Primene (227 +/- 27 vs. 192 +/- 42 micromol.kg(-1).h(-1)). CONCLUSIONS: Primene administration results in lower leucine released from proteins, an estimate of protein breakdown, than Trophamine in preterm infants. Increases in whole body leucine turnover in response to administration of i.v. amino acids is influenced by the composition of the amino acid mixture. The factors responsible for this difference remain to be elucidated.     

Energy expenditure and energy intake during dexamethasone therapy for chronic lung disease.

Dexamethasone is commonly administered to ventilator-dependent preterm infants with chronic lung disease. Infants receiving dexamethasone therapy frequently exhibit decreased rates of weight gain. The purpose of this investigation was to determine whether decreased growth in infants receiving dexamethasone therapy is caused by increased energy expenditure. Twelve infants were studied: 6 received dexamethasone treatment at 2 wk of age and crossed over to receive placebo treatment at 4 wk; the treatment order was reversed in the other 6 infants. The doubly labeled water method was used to determine energy expenditure for a 1-wk period during each treatment phase. The rate of weight gain during dexamethasone treatment was 6.5+/-10.6 and 20.0+/-5.7 g/kg/d during placebo treatment. Energy expenditure was 93.1+/-34.6 kcal/kg/d during dexamethasone treatment and 88.3+/-37.1 kcal/kg/d during placebo treatment. Energy intake was 119.2+/-29.0 kcal/kg/d during dexamethasone treatment and 113.8+/-23.7 kcal/kg/d during placebo treatment. The difference between intake and expenditure, or the energy available for growth, was 26.2+/-36.8 kcal/kg/d during dexamethasone treatment and 25.5+/-37.4 kcal/kg/d during placebo treatment. No significant differences were found in energy expenditure or energy intake between the treatment phases. The reduced growth seen in infants receiving dexamethasone treatment cannot be explained by increased energy expenditure or decreased energy intake, but may be due to differences in the composition of newly accreted tissue.     

Incidence and predicting factors of hypozincemia in very-low-birth-weight infants at near-term postmenstrual age

We prospectively investigated serum zinc (Zn) concentrations and clinical factors in 118 very-low-birth-weight infants with a gestational age of 29.5 +/- (SD) 2.5 weeks and a birth weight of 1,194 +/- 254 g at near-term postmenstrual age. The 25th percentile of the serum Zn concentration was 7.0 micromol/l. The infants whose serum Zn concentrations were less than 7.0 micromol/l (defined as hypozincemia) did not have apparent symptoms of Zn deficiency. Multivariate logistic regression analyses demonstrated that hypozincemia was associated with factors such as weight gain (1-g/kg/day increase of weight; OR 1.1762, 95% CI 1.0414-1.3286) and serum albumin concentration (1-g/dl increase of serum albumin; OR 0.0816, 95% CI 0.0152-0.4372). The types of milk feeding did not affect the serum Zn concentrations in the study subjects. This study suggests that hypozincemia in very-low-birth-weight infants at near-term postmenstrual age is associated with greater weight gain and lower serum albumin concentration. Nutritional supply of Zn by human milk fortifier and preterm formula does not appear to meet the demands of rapidly growing very-low-birth-weight infants.     

Zinc absorption, distribution, excretion, and retention by healthy preterm infants

Zinc (Zn) is an essential nutrient for growth, but little is known about Zn absorption, distribution, excretion, and retention in preterm infants. Nine infants with gestational age 32+/-1 wk (mean+/-SE), birth weight 1.44+/-0.08 kg, postnatal age 14+/-3 d, on Zn intake of 23+/-3 micromol/kg per d via enteral feeding of preterm formula were studied. A stable Zn isotope (70Zn) was administered orally or i.v., and plasma, red blood cells, urine, and feces were sampled for up to 30 d. Samples were analyzed for Zn by inductively coupled plasma atomic emission spectrometry and for isotope enrichment by inductively coupled plasma mass spectrometry. Data were analyzed by compartmental analysis using the Simulation Analysis and Modeling program, and absorption, distribution, excretion, and retention were calculated. Absorption was 36+/-5% or 7+/-1 micromol/kg per d; distribution in plasma was 15+/-1 micromol Zn/L and in RBC was 41+/-4 micromol Zn/L; excretion in urine was 0.55+/-0.03 micromol Zn/kg per d and in feces was 17+/-3 micromol Zn/kg per d and retention was 5+/-1 microl/kg per d. Results show that healthy preterm infants with Zn intake of 23 micromol/kg per d and expected growth rates (> 15 g/kg per d) absorb and retain Zn at rates comparable to in utero accretion. The values for absorption, distribution, and excretion by this population of healthy preterm infants provide a normal range for future studies, although further studies are required to determine endogenous excretion rates in healthy preterm infants. We speculate that these values can be used to determine whether Zn kinetics are abnormal in sick infants or in infants with slow growth.     

Effect of preeclampsia in the mother on the leucine metabolism in the newborn infant.

The leucine turnover in newborn infants is influenced by factors such as nutritional state and corticosteroid treatment. Little is known about maternal factors influencing the leucine turnover in the newborn. In order to approach the effect of preeclampsia in the mother on neonatal protein turnover, we studied the leucine turnover in preterm infants soon after birth and again after 7 days. Ten infants from preeclamptic mothers (birth weight 1,280 +/- 240 g, gestational age 31 +/- 2 weeks) and 15 control patients (birth weight 1,320 +/- 210 g, gestational age 30 +/- 2 weeks) were enrolled. The leucine turnover was measured using a primed constant 5-hour intravenous infusion of [1-(13)C]leucine within the first 24 h after delivery and again on day 7 of life. The turnover (leucine flux; micromol.kg(-1).h(-1)) was calculated from the enrichment in alpha-ketoisocaproic acid in plasma. The leucine turnover on day 1 was 300 +/- 65 in the preeclampsia group and 358 +/- 70 in the controls (ANOVA, p < 0.05). The values on day 7 were 474 +/- 73 in the preeclampsia group and 485 +/- 80 in the control group (n.s.). To conclude, the leucine turnover on day 1 is lower in infants of preeclamptic mothers as compared with controls. This difference has disappeared on day 7 of life after receiving the same protein and energy intake.     

Effect of minimal enteral feeding on splanchnic uptake of leucine in the postabsorptive state in preterm infants

We conducted a controlled, randomized trial to study the effect of minimal enteral feeding on leucine uptake by splanchnic tissues, as an indicator of maturation of these tissues, in preterm infants in the first week of life. Within a few hours after birth, while receiving only glucose, a primed constant infusion of [1-(13)C]-leucine was started and continued for 5 h via the nasogastric tube, whereas 5,5,5 D3-leucine was infused intravenously (for both tracers, priming dose 2 mg/kg, continuous infusion 2 mg/kg/h). Patients were thereafter randomized to receive solely parenteral nutrition (C), parenteral nutrition and 20 mL breast milk/kg/d (BM), or parenteral nutrition and 20 mL formula/kg/d (F). On d 7, the measurements were repeated, after discontinuing the oral intake for 5 h. Fourteen infants were included in group C, 12 in group BM, and 12 in group F. There was no difference in energy intake or nitrogen balance at any time. On d 1, plasma enrichment for the nasogastric tracer was lower than for the intravenous tracer for all three groups, both for leucine and for alpha-keto-isocaproic acid. On d 7, the enrichment for leucine and alpha-keto-isocaproic acid for the nasogastric tracer was lower than for the intravenous tracer for the groups BM and F (BM: 3.65 +/- 1.20 nasogastric versus 4.64 +/- 0.64 i.v.; F: 4.37 +/- 1.14 nasogastric versus 5.21 +/- 0.9 i.v.). In the control group, there was no difference between tracers. The lower plasma enrichment for the nasogastric tracer compared with the intravenous tracer suggests uptake of leucine by the splanchnic tissues. We conclude that minimal enteral feeding--even in low volumes of 20 mL/kg/d--increases the leucine uptake by the splanchnic tissue. We speculate that this reflects a higher protein synthesis of splanchnic tissues in the groups receiving enteral nutrition.     

Parenteral glycerol enhances gluconeogenesis in very premature infants

We have previously demonstrated that very premature infants receiving total parenteral nutrition maintain normoglycemia primarily by glucose produced via gluconeogenesis and that the lipid emulsion is most important in supporting gluconeogenesis. It is, however, not clear whether this is a result of the glycerol or the fatty acid constituent. The purpose of the present study was to determine the effect of intravenous supplemental glycerol alone on glucose production and gluconeogenesis. Twenty infants (birth weight, 1014 +/- 32 g; gestational age, 27 +/- 1 wk) were studied on d 4 +/- 1 (mean +/- SE). All infants received glucose at 17 micromol/kg x min for 9 h (after an initial study hour with 33 micromol/kg x min). Eight infants received no additional substrate during the study, and 12 infants received supplemental glycerol at 5 (n = 6) or 10 micromol/kg x min (n = 6) over the last 5 h of study. In infants receiving glucose alone, between period 1 (study hours 4-5) and period 2 (study hours 9-10), rates of glucose production ([U-13C]glucose) decreased from 12.9 +/- 1.2 to 7.4 +/- 0.9 micromol/kg x min (p < 0.01). This was the result of decreased glycogenolysis but no change in gluconeogenesis ([U-13C]glucose mass isotopomer distribution analysis) (5.1 +/- 0.6 versus 5.7 +/- 0.4 micromol/kg x min) (ns). Glycerol infusion at 5 and 10 micromol/kg x min, respectively, maintained glucose production (despite comparable decrease in glycogenolysis) by increasing gluconeogenesis from 4.3 +/- 0.2 to 6.3 +/- 0.5 (p < 0.03), and 6.0 +/- 0.7 to 8.8 +/- 0.8 micromol/kg/min (p < 0.01). In very premature infants, parenteral glycerol enhances gluconeogenesis and attenuates time dependent decrease in glucose production.     

Effect of insulin with oral nutrients on whole-body protein metabolism in growing pubertal children with type 1 diabetes

Insulin treatment of children with insulin-dependent diabetes mellitus improves whole body protein balance. Our recent study, conducted in pubertal children with type 1 diabetes with provision of both insulin and amino acids, indicated a positive effect of insulin on protein balance, primarily through decreased protein degradation. The current study was undertaken to assess the effect of insulin on protein metabolism in adolescents with type 1 diabetes during oral provision of a complete diet. Whole-body protein metabolism in six pubertal children (13-17 y) with type 1 diabetes mellitus was assessed with L-[1-13C]leucine during a basal (insulin-withdrawn) period and during infusion of 0.15 U/kg/h regular insulin with hourly meals to meet protein and energy requirements. Net leucine balance was significantly higher with insulin and nutrients (13.1 +/- 6.3 micromol leucine/kg/h) than in the basal state (-21.4 +/- 2.8, p < 0.01) with protein degradation decreased from 138 +/- 5.6 mumol leucine/kg/h to 108 +/- 5.9 (p < 0.01) and no significant change in protein synthesis. Even with an ample supply of nutrients, insulin does not increase whole-body protein synthesis in pubertal children with type 1 diabetes mellitus and positive protein balance is solely due to a substantial reduction in the rate at which protein is degraded.     

Increased parenteral amino acid administration to extremely low-birth-weight infants during early postnatal life

BACKGROUND: Early administration of parenteral amino acids to infants with extremely low birth weight (birth weight < or = 1,000 g) has been encouraged to foster growth. However, excessive intravenous intake of amino acids may cause metabolic acidosis and uremia in extremely low birth weight infants. The hypothesis for this study was that extremely low birth weight infants would tolerate slightly increased early postnatal parenteral amino acid administration and benefit. METHODS: The peak daily parenteral amino acid dosage was increased from 3 g/kg (standard group) to 4 g/kg (modified group). The corrected parenteral amino acid dosage was computed to account for enteral protein intake and keep the combined daily intravenous amino acid and enteral protein intake at or below 3 g . kg -1 . d -1 in the standard group and 4 g . kg -1 . d -1 in the modified group. The primary outcome measure was plasma bicarbonate concentration as an indicator of acid-base status. Data were collected for patient demographics, nutritional intake, serum bicarbonate and serum urea nitrogen concentrations, and outcome. RESULTS: The corrected parenteral amino acid intake of the modified group was 16% greater at postnatal week 1 (3.30 +/- 0.83 g . kg -1 . d -1; mean, +/-1 SD) and 18% greater (3.86 +/- 0.94 g . kg -1 . d -1 ) at postnatal week 2 than the parenteral amino acid intake of the standard group. In the modified group, the mean serum bicarbonate concentration was 19.1 +/- 1.8 mEq/dL at week 1 and 23.9 +/- 2.9 mEq/dL at week 2, with no difference between the groups. At week 1, serum urea nitrogen concentrations were the same in both groups. The mean serum urea nitrogen concentration of the modified group at postnatal week 2 (18.2 +/- 8.8 mg/dL) was unchanged from postnatal week 1, but was greater than that of the standard group at postnatal week 2. Weight gain was the same in both groups. Corrected parenteral amino acid intake at postnatal week 1 correlated directly with weight gain from birth to postnatal week 2 ( P < 0.03) in both groups. CONCLUSIONS: Infants with extremely low birth weight tolerated parenteral amino acid intake of approximately 4 g . kg -1 . d -1. Mild increases of mean serum urea nitrogen concentration and mean weight gain were associated with increased parenteral amino acid administration without significant acidosis.     

Minimum protein intake for the preterm neonate determined by protein and amino acid kinetics

Lower limits of protein needs in prematurely born neonates have not been adequately studied, yet providing protein in amounts maximizing accretion without excess is a goal in these infants' nutritional care. We hypothesized that with the use of amino acid oxidation methodology, it would be possible to define minimum protein requirement. Our objective was to investigate protein kinetics during short-term changes in protein intake by measurement of nitrogen balance and amino acid flux and oxidation using [(15)N]glycine, [(13)C]phenylalanine, and [(13)C]leucine tracers. Protein kinetics were examined in 21 preterm infants (gestational age: 29 +/- 3 wk; birth weight: 1091 +/- 324 g) at five protein intakes (1.0, 1.5, 2.0, 2.5, and 3.0 g x kg(-1) x d(-1)) with 1 d of adaptation to the test intakes. From nitrogen balance data, a protein need of 0.74 g x kg(-1 x -1) was estimated to achieve zero balance. For all three amino acids, flux and oxidation estimates were not different across protein intakes. Whole-body protein synthesis and breakdown estimates from [(15)N]ammonia data were 14.6 +/- 3.4 and 14.4 +/- 4.1 g x kg(-1) x d(-1), respectively. Glycine flux (680 +/- 168 micromol x kg(-1) x h(-1)) was greater than leucine flux (323 +/- 115 micromol x kg(-1) x h(-1)), which was greater than phenylalanine flux (84.3 +/- 35.2 micromol x kg(-1) x h(-1)). Leucine oxidation (36.7 +/- 15.6 micromol x kg(-1) x h(-1)) was also greater than phenylalanine oxidation (6.64 +/- 4.41 micromol x kg(-1) x h(-1)). Infants in our study were able to adapt to short-term changes in protein intake with little consequence to the overall whole-body protein economy, as measured by the three test amino acids.     

Evaluation of a netilmicin-loading dose in very low birthweight infants

BACKGROUND: The bactericidal efficacy of aminoglycosides is directly related to maximum serum concentrations, particularly the initial one. Therefore, several groups have recommended an aminoglycoside loading dose. Our goal was to develop a simplified dosage regimen for preterm infants which would result in therapeutic maximum serum concentrations early in the course of therapy. METHODS: Open, noncomparative study during November 2000 to April 2001. The modified netilmicin-dosing protocol included a loading dose of 5 mg/kg in the first week of life, followed by a maintenance regimen of 3.5 mg/kg every 24 h. After the first week of life the corresponding doses were 6 (loading) and 5 mg/kg (maintenance). A peak level was measured 30 min after the second dose, and a trough level immediately before the third dose. RESULTS: Thirty-five very low birthweight infants (mean birthweight 876 +/- 170, range 536-1,385 g; mean gestational age 26 +/- 1.8, range 23-30 weeks) who had 46 episodes of netilmicin treatment were included in the analysis. Mean netilmicin peak and trough values were 15.9 +/- 3.7 (range 8.9-28.9) and 3.4 +/- 1.3 (range 1.0-7.8) micromol/l, respectively. Ninety-one percent of all peak levels were within the targeted range of > or =10 micromol/l. Eleven trough values (24%) were > or =4 micromol/l: in 7 instances netilmicin was administered within the first week of life, 5 of these patients had concomitant indomethacin treatment. Only 1 of the 35 neonates had a rise in serum creatinine of > or =0.5 mg/dl during netilmicin therapy. Hearing evaluations were performed in 25 of the 29 surviving infants at discharge home, all of which gave normal results. CONCLUSIONS: The new netilmicin-dosing protocol yielded therapeutic maximum serum concentrations in 91% of cases after the second dose. However, a significant number of very low birthweight infants had elevated trough levels, particularly when netilmicin was administered in the first week of life with concomitant indomethacin treatment. We speculate that a longer interval between the loading dose and the first maintenance dose would result in fewer elevated trough levels with a similarly high number of therapeutic peak levels.     

Cardiovascular effects of low-dose dexamethasone in very low birth weight neonates with refractory hypotension

BACKGROUND: Administration of hydrocortisone and relatively high doses of dexamethasone increase blood pressure in volume- and pressor-resistant hypotensive preterm infants. However, little is known about the temporal relationship of dexamethasone administration and the improvement in blood pressure and the weaning of pressors/inotropes. Furthermore, there are no sufficient data available on whether a smaller dose of dexamethasone would also be effective in treating refractory hypotension. OBJECTIVE: To study the cardiovascular responses to low-dose dexamethasone in very low birth weight neonates with volume- and pressor-resistant hypotension. METHODS: Retrospective database review. Twenty-four preterm neonates (gestational age 26 (23-34) weeks; birth weight 801 (457-1,180) g; postnatal age 2 (1-24) days, medians (ranges)) who remained hypotensive despite volume administration and combined dopamine and dobutamine treatment at >or=30 microg/kg/min received dexamethasone 0.1 mg/kg followed by 0.05 mg/kg intravenously every 12 h for 5 additional doses if still on pressors >or=8 microg/kg/min. RESULTS: Two hours after the first dose of dexamethasone the mean blood pressure increased from 30 +/- 5 to 34 +/- 6 mm Hg (p < 0.001) and remained elevated at 4, 6, 12, and 24 h after treatment was started (p < 0.001). Six hours after the initial dose of dexamethasone the pressor/inotrope requirement decreased from 34 +/- 9 to 24 +/- 13 microg/kg/min (p = 0.001) and continued to decrease at 12 and 24 h (p < 0.001). Urine output also increased significantly during the first 6 h after dexamethasone (p < 0.001). CONCLUSIONS: Low-dose dexamethasone rapidly increases blood pressure and decreases pressor requirements in very low birth weight neonates with volume- and pressor-resistant hypotension.     

Dietary glutamate is almost entirely removed in its first pass through the splanchnic bed in premature infants

Breast milk glutamate is a potential gluconeogenic substrate. However, in piglets, most dietary glutamate undergoes first pass extraction by the gut, limiting its contribution to glucose formation. The objectives of the study were to determine in preterm infants, whether dietary glutamate increases plasma [glutamate] in a dose-dependent fashion and whether glutamate carbon appears in plasma glucose to an appreciable extent. Five enterally fed infants (31 +/- 0 wk; 1555 +/- 131 g) (mean +/- SE) were studied twice (postnatal age 10 +/- 1 d and 17 +/- 1 d, respectively), while receiving an intragastric infusion of glutamate (labeled to 4% +/- by [U-13C] glutamate) at 2.4 (study 1) and 4.8 micromol/kg/min (study 2) for 1.5 h (n=2) or 5 h (n=3). Plasma [glutamate] was 82 +/- 8 microM at baseline, and 84 +/- 11 and 90 +/- 13 microM after glutamate supplementation at 2.4 and 4.8 micromol/kg/min, respectively, values not different from baseline. Plasma [glutamate] was not affected by the duration of the glutamate infusion (1.5 versus 5 h). Plasma 13C glucose enrichment was only 0.3% (after 5 h ingestion of glutamate labeled to 4%) indicating insignificant contribution of dietary glutamate carbon to glucose. Thus, in premature infants, splanchnic extraction is the major fate of dietary glutamate, which is not a significant gluconeogenic substrate in these infants.     

A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance

To determine whether a continuous insulin infusion improves glucose tolerance in extremely low birth weight infants, we conducted a prospective, randomized trial in 24 neonates 4 to 14 days old (mean birth weight 772.9 +/- 128 gm; mean gestational age 26.3 +/- 1.6 weeks). Infants who had glucose intolerance were randomly assigned to receive either intravenous glucose and total parenteral nutrition with insulin through a microliter-sensitive pump or standard intravenous therapy alone. One infant assigned to receive insulin never required it. The groups were similar in birth weight, gestational age, race, gender, medical condition, and energy intake before the study. The mean duration of therapy was 14.6 days (range 7 to 21 days). During the study, the 11 insulin-treated infants tolerated higher glucose infusion rates (20.1 +/- 2.5 vs 13.2 +/- 3.2 mg/kg/min (1.1 +/- 0.1 vs 0.7 +/- 0.2 mmol/L); p less than 0.01), had greater nonprotein energy intake (124.7 +/- 18 vs 86.0 +/- 6 kcal/kg/day; p less than 0.01), and had better weight gain (20.1 +/- 12.1 vs 7.8 +/- 5.1 gm/kg/day; p less than 0.01) than the 12 control infants. The incidence of hypoglycemia, electrolyte imbalance, chronic lung disease, and death did not differ between groups. We conclude that a controlled insulin infusion improves and sustains glucose tolerance, facilitates provision of calories, and enhances weight gain in glucose-intolerant premature infants.     

Pharmacokinetic observations of phenytoin disposition in the newborn and young infant

The pharmacokinetic profile of phenytoin (DPH) was studied in 30 infants aged 2 days to 96 weeks. The plasma DPH half-life during the first week of life in term infants was prolonged and very variable (20-7 +/- 11-6 h, mean +/-SD). Thereafter the plasma half-life was much shorter (7-6 +/- 3-5 h). In preterm infants the half-life was much longer (75-4 +/- 64-5 h) and more variable. The mean apparent volume of distribution was similar in these groups of infants: preterm newborn 0-80 +/- 0-22 l/kg, term infants during the first week of life 0-80 +/- 0-26 l/kg, and term infants greater than 2 weeks of age 0-73 +/- 0-18 l/kg. Predictions of steady-state plasma DPH concentrations, based on these kinetic parameters, were confirmed. Very low "trough" plasma DPH concentrations were observed after the 14th postnatal day in 19 infants receiving 8 mg/kg per 24 h orally. On the other hand, infants of less than one week of age receiving the same dose, especially if preterm, frequently showed drug accumulation to toxic plasma DPH concentrations. The impaired binding of DPH to newborn plasma protein was confirmed but "normal adult values" were approached by the age of 3 months. An intravenous loading dose of 8 mg/kg (sodium phenytoin) can be expected to generate a mean plasma DPH concentration of 10 mg/l (40 micronmol/l) in the newborn. Loading doses of up to 12 mg/kg were given without untoward effects. During the first week or so of life plasma Dph half-life is so variable that no fixed dosage regimen can be derived from the available data. Beyond the second week of life, however, a dose of 8 mg/kg per 24 h is probably inadequate for most infants.     

Pharmacokinetic observations of phenytoin disposition in the newborn and young infant.

The pharmacokinetic profile of phenytoin (DPH) was studied in 30 infants aged 2 days to 96 weeks. The plasma DPH half-life during the first week of life in term infants was prolonged and very variable (20-7 +/- 11-6 h, mean +/-SD). Thereafter the plasma half-life was much shorter (7-6 +/- 3-5 h). In preterm infants the half-life was much longer (75-4 +/- 64-5 h) and more variable. The mean apparent volume of distribution was similar in these groups of infants: preterm newborn 0-80 +/- 0-22 l/kg, term infants during the first week of life 0-80 +/- 0-26 l/kg, and term infants greater than 2 weeks of age 0-73 +/- 0-18 l/kg. Predictions of steady-state plasma DPH concentrations, based on these kinetic parameters, were confirmed. Very low "trough" plasma DPH concentrations were observed after the 14th postnatal day in 19 infants receiving 8 mg/kg per 24 h orally. On the other hand, infants of less than one week of age receiving the same dose, especially if preterm, frequently showed drug accumulation to toxic plasma DPH concentrations. The impaired binding of DPH to newborn plasma protein was confirmed but "normal adult values" were approached by the age of 3 months. An intravenous loading dose of 8 mg/kg (sodium phenytoin) can be expected to generate a mean plasma DPH concentration of 10 mg/l (40 micronmol/l) in the newborn. Loading doses of up to 12 mg/kg were given without untoward effects. During the first week or so of life plasma Dph half-life is so variable that no fixed dosage regimen can be derived from the available data. Beyond the second week of life, however, a dose of 8 mg/kg per 24 h is probably inadequate for most infants.     

Changes in protein turnover after the introduction of parenteral nutrition in premature infants: comparison of breast milk and egg protein-based amino acid solutions.

Rates of protein turnover were measured in 20 infants receiving either Vamin Infant (group A) or Vamin 9 glucose (group B) as the amino acid source in total parenteral nutrition. A constant infusion of L-[1-13C]leucine was used to measure whole body leucine flux, and leucine oxidation rates were derived from measurements of total urinary nitrogen excretion. Infants were first studied when receiving only i.v. glucose and again on each of the next 4 d as total parenteral nutrition was gradually increased to a maximum of 430 mg nitrogen/kg/d and 90 nonprotein kcal/kg/d. Net protein gain and protein synthesis and breakdown rates increased progressively for all infants taken together over the study period as i.v. nutrition was increasing (p less than 0.001). There were no differences between groups in the changes in net protein gain and rates of protein synthesis and breakdown throughout the study period. Nitrogen retention on d 5 for the two groups was similar (60 +/- 16% and 67 +/- 11% in groups A and B, respectively). In a subgroup of infants, measurements were repeated on d 8, when the intake had been constant for 3 d. Protein retention was the same as on d 5, but both synthesis and breakdown were increased. It is concluded that rates of protein turnover increase significantly in response to increasing i.v. nutrition and that this elevation was not influenced by the composition of the amino acid mixture given.     

The role of parenteral lipids in supporting gluconeogenesis in very premature infants

We have previously demonstrated that very premature infants receiving glucose at 17 micromol/kg min plus appropriate supply of parenteral lipids (Intralipid) and amino acids (TrophAmine) maintained normoglycemia by glucose produced primarily via gluconeogenesis. The present study addressed the individual roles of parenteral lipids and amino acids in supporting gluconeogenesis. Fourteen premature infants (993 +/- 36 g 27 +/- 1 wk) (mean +/- SE) were studied for 8 h on d 5 +/- 1 of life. All infants were receiving standard TPN prior to the study. At start of study, the glucose infusion rate was decreased to approximately 17 micromol/kg min and either Intralipid (g + AA; n = 8) or TrophAmine (g + IL; n = 6) was discontinued. Data from 14 previously studied infants receiving glucose (approximately 17 micromol/kg min) + TrophAmine + Intralipid (g + AA + IL) are included for comparison. Gluconeogenesis was measured by [U-13 C]glucose, (g + AA) and (8 infants of the g + AA + IL group) or [2-13C]glycerol, (g + IL) and (6 infants of the g + AA + IL group). Infants studied by the same method were compared. Withdrawal of Intralipid resulted in decreased gluconeogenesis, 6.3 +/- 0.9 (g +AA) vs. 8.4 +/- 0.7 micromol/kg min (g + AA + IL) (p = 0.03). Withdrawal of TrophAmine affected neither total gluconeogenesis, 7.5 +/- 0.8 vs. 7.9 +/- 0.9 micromol/kg min nor gluconeogenesis from glycerol, 4.4 +/- 0.6 vs. 4.9 +/- 0.7 micromol/kg min (g+ IL and g + AA + IL groups, respectively). In conclusion, in parenterally fed very premature infants, lipids play a primary role in supporting gluconeogenesis.     

Early dexamethasone decreases expression of activation markers on neutrophils and monocytes in preterm infants

AIM: To investigate the effects of early dexamethasone administration on activation of circulating neutrophils and monocytes in preterm infants with respiratory distress syndrome requiring treatment with surfactant. METHODS: Neonates (n = 30) with respiratory distress were randomized to receive dexamethasone (DEX group, 29.1 +/- 1.2 wk, 1223 +/- 156 g, n = 15) from the first postnatal day, or to serve as controls (control group, 29.2 +/- 1.4 wk, 1250 +/- 148 g, n = 15). Dexamethasone was given as a 4 d course (0.5 mg kg(-1) on postnatal days 1 and 2, and 0.25 mg kg(-1) on days 3 and 4). Polymorphonuclear leucocyte (PMN) and monocyte surface expression of CD11b, L-selectin and CD14 was quantified with flow cytometry, and plasma macrophage-inflammatory protein-1alpha (MIP-1alpha) with an enzyme-linked immunosorbent assay. Blood samples were collected on days 1, 2-3 and 5-7. RESULTS: In the DEX group 1/15, and in the control group 7/15 developed bronchopulmonary dysplasia (p < 0.04). PMN CD11b (median 100, range 70-190 vs 154, 96-213, p=0.01), monocyte CD14 (235, 102-433 vs 355, 219-533, p=0.01) and plasma MIP-1alpha (20 ng l(-1), 20-32 vs 37 ng l(-1), 20-70, p = 0.005) were lower in the DEX group at days 2-3. All adhesion molecule expression and plasma MIP-1alpha levels were comparable at days 5-7, with the exception of monocyte L-selectin expression levels, which remained lower in the DEX group. CONCLUSION: In preterm infants with respiratory distress syndrome, early dexamethasone causes downregulation of PMN and monocyte activation. This may attenuate pulmonary inflammation and improve pulmonary outcome.     

Insulin infusion with parenteral nutrition in extremely low birth weight infants with hyperglycemia

From Nov. 7, 1983, to Nov. 6, 1986, all infants with birth weight less than or equal to 1000 gm admitted to Oregon Health Sciences University who had persistent hyperglycemia and glycosuria were treated with graded insulin infusion while energy intake was increased to at least 100 kcal/kg/day (419 kilojoules/kg/day). The records of these infants were reviewed to define the clinical characteristics of infants likely to develop hyperglycemia and to see whether insulin administration would allow goals for energy intake to be met. There were 76 surviving infants; 34 received insulin and 42 did not. Treated infants were smaller (767 +/- 161 vs 872 +/- 98 gm; p = 0.0004), were more immature (26.8 +/- 1.4 vs 27.7 +/- 2.0 weeks; p = 0.0115), and required mechanical ventilation longer (28 +/- 19 vs 17 +/- 15 days; p = 0.0196). There were no significant differences between the groups at 3, 7, 10, or 14 days for intravenously administered glucose or for total nonprotein energy intake at 3, 7, 10, 14, 28, or 56 days. Treated infants achieved an intake of 100 kcal/kg/day (419 kilojoules/kg/day) at 15 +/- 8 vs 17 +/- 11 days and regained birth weight at 12 +/- 6 vs 13 +/- 6 days (NS). There was no difference in percent change from birth weight at 7, 14, 28, or 56 days. Treated infants had a glucose concentration of 195 +/- 60 mg/dl (10.8 +/- 3.3 mmol/L) while receiving 7.9 +/- 3.0 mg/kg/min (43 +/- 17 mumol/kg/min) of glucose at the start of insulin infusion on days 1 to 14. Insulin was given for 1 to 58 days. The initial dose was 40 to 100 mU/gm of dextrose infused (57 to 142 nmol/mol) and then gradually decreased. Less than 0.5% of blood glucose values were 25 to 40 mg/dl (1.4 to 2.2 mmol/L). We conclude that insulin infusion improves glucose tolerance in extremely low birth weight infants and allows hyperglycemic infants to achieve adequate energy intake similar to that of infants who do not become hyperglycemic.