Because of immaturity of the gastrointestinal tract, most prematurely born infants must initially be given parenteral nutrition (PN). PN can be given safely shortly after birth (aggressive PN). The purpose of this study was to evaluate the effectiveness and safety of aggressive PN in VLBW infants during the first week of life in comparison with standard PN. We hypothesized that, in comparison to standard PN, aggressive PN would improve nitrogen balance, be well tolerated metabolically, shorten time to regain birth weight and shorten length of hospitalization.

This randomized controlled trial was conducted in a 40 bed level III referral neonatal unit. All babies admitted from October 2009 to March 2010 were screened for eligibility. Eligibility criteria were: (i) Prematurity (<37 weeks), (ii) chronological age <24 hours, (iii) birth weight <1500 grams and (iv) need for respiratory support (mechanical ventilation or nasal CPAP). Babies with any one of the following were excluded: (i) major congenital defects, (ii) chromosomal abnormalities, (iii) antenatal suspicion of liver and or kidney diseases, (iv) enrolment to other trial. If informed consent was obtained from one or both parents within the first 24 hours of life, infants were enrolled. The study protocol was approved by institutional ethics committee.

Body weight was determined daily on an electronic scale accurate to 2　g (ATCO, Electric Balance, Model LL6MM 06/12-W). Fluid intake and urine volume was recorded daily. Urine was collected from an attached bag with any leakage collected on preweighed diaper.

Nitrogen retention was determined on days 4 and 7 using the standard formula (5). Nitrogen intake was calculated as Amino acids (g) ÷ 6.25 = mg of nitrogen. To monitor tolerance of PN, blood glucose was determined twice daily and serum electrolytes, urea, creatinine, bilirubin, triglycerides, arterial blood gas and full blood count were obtained on days 4 and 7. Determinations were performed in the hospital laboratory using standard methods. The attending neonatologist could order additional tests as needed depending on the clinical condition of baby. Time (in days) to regain birth weight and length of hospitalization were determined from medical records.

Statistical Package for Social Sciences (SPSS version 11.5, Inc. Chicago, USA) for MS windows was used for statistical analysis. Nitrogen retention on day 7 with standard PN, estimated before the start of the trial, was 150 (+/- 80) mg/kg/day. It was hypothesized that aggressive PN would increase this to 300 mg/kg/day on day 7. Sample size of 16 in each group was necessary to detect this difference in the mean nitrogen retention with a power of 80% and a P value < 0.05.

During study period 34 babies met the eligibility criteria and were enrolled with 17 babies in each group. Mean birth weight was 1161.5 (SD 223.8) in the aggressive PN group and 1263.8 (SD 194.4) in the standard PN group. Mean gestational age was 30.5 (2.6) weeks and 32.1 (2.8) weeks, respectively. In both groups 41% babies received antenatal steroids.

Table I shows nutritional intakes and outcomes of both groups. Biochemical parameters were comparable in both groups (Table II). Clinical outcomes like intraventricular hemorrhage, hemodynamically significant PDA, late onset sepsis, need for exchange transfusion and bronchopulmonary dysplasia were comparable in both groups. Two babies in the aggressive group and one baby in the standard group died before discharge (P=0.9).

TABLE I Nutritional Outcomes In The Two Groups

TABLE II	Biochemical Parameters on Day 7 in The Two Groups

Though the average daily calorie intake was significantly higher in the aggressive PN group, nitrogen retention in the first week was not significantly increased. Trends were seen toward shorter time to reach full feeds and to regain birth weight and toward shorter duration of stay in NICU. Most importantly, aggressive PN was well tolerated and no adverse clinical and biochemical outcomes were noted.

Early amino acid administration has previously been shown to be safe [6-8]. Early amino acid administration increases protein synthesis, resulting in an anabolic state [9]. Early lipid administration has not been associated with adverse effects in preterm neonates [10,11]. Ibrahim, et al. [5] showed that early administration of both amino acids and lipids is well tolerated. Their aggressive approach improved nitrogen balance of preterm babies compared to babies who received late PN. We compared our aggressive approach with the existing PN regimen, where infants received amino acids from day one but at a lower dose than with the aggressive regimen. Nitrogen excretion increases in babies when nitrogen intake increases [8]. We noted a similar finding. There was also nitrogen coming from enteral feedings which probably increased urinary nitrogen excretion and explains why apparent nitrogen retention was less. This may be one of the reasons why we could not show significant improvement in nitrogen retention.

Recent studies have demonstrated better growth in VLBW babies receiving aggressive nutrition [7,12-14]. We could not find an effect of aggressive PN on time to regain birth weight. Most babies in the aggressive PN group were on full enteral feeds by the ninth day. But as per unit policy, most babies did not receive fortified milk till the end of second week. There are other factors influencing weight in the first week of life. These may be the reason why we did not find an effect on time to regain birth weight. Valentine, et al. [7] observed that babies receiving early amino acids achieved full enteral feedings earlier despite being smaller and younger at birth. We noticed a similar trend, though it was not significant. In developing countries like India, social and economic reasons affect the time of discharge. So we could not show any effect on duration of NICU stay.

One important observation was that babies tolerated aggressive PN well. Neonatologists in developing countries like India, are still concerned about the safety of PN, as there is lack of data from the developing world. We can say that aggressive and early PN is feasible and safe in India. This may be taken as a positive step. Larger multicentric trials are needed before reaching conclusions about efficacy. Our study suggests that aggressive PN is safe in India.

Acknowledgement: Prof Ekhard Ziegler, Fomon Infant Nutrition Unit, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City.

Contributors: AT: conceived the study, helped in statistical analysis and wrote the manuscript; MW: collected data and helped in statistical analysis; UV: supervised data collection. The final manuscript was approved by all authors.

Funding: None; Competing interest: None stated.