Raimondi, Francesco; Spera, Anna Maria; Sellitto, Maria; Landolfo, Francesca; Capasso, Letizia
Background and Aim: Very-low-birth-weight (VLBW) neonates may develop severe intolerance to standard preterm formula especially if they are associated with intrauterine growth restriction (IUGR). We tested the hypothesis that these infants may tolerate an elemental, amino acid–based formula as a rescue feeding strategy.
Methods: In a prospective, case-control pilot study, we enrolled VLBW IUGR infants enterally fed with standard preterm formula (SPF) at daily increments of 16 mL/kg. If gastric residuals accounted for >70% of milk feed in the previous 24 hours, then feedings were temporarily withheld and then resumed with amino acid formula (AAF) increased at the same speed. Cases on AAF were compared to controls on SPF and with cases themselves while on SPF. Primary outcome was the time to reach full enteral feedings. Secondary outcomes were time on parenteral nutrition, time on central venous catheter, and formula tolerability based on the amount of gastric residual volume.
Results: Sixty-four infants (22 cases) were enrolled. Although during the total duration of nutrition, cases had worse primary and secondary outcomes, when on AAF, cases were comparable to controls in time to full enteral feeding (14.4 vs 14 days), time on parenteral nutrition, and time on central venous catheter. Cases on AAF and controls had similar gastric residual volumes. At day 3 after AAF introduction, cases had a significantly reduced number (%) of gastric residual volume >5 mL/kg over total number of feedings (5.6 vs 1.5%; P < 0.05) and the mean gastric residual volume (2.7 vs 0.6 mL; P < 0.05) compared to themselves while on SPF. No difference was detected in weight at 21 and 28 days, in main serum parameters and outcome at discharge. Growth at 12 months of corrected age was also comparable.
Conclusions: In our population of VLBW IUGR newborns with severe feeding intolerance, a short course on AAF was a safe and effective means of nutritional rescue.
Very-low-birth-weight (VLBW) neonates with intrauterine growth restriction (IUGR) often may have a severely impaired intestinal function (1,2). The preterm gut is further affected by the adverse blood redistribution that occurs in fetuses with an IUGR. After birth, these infants frequently react to enteral feedings with abdominal distension, increasing volumes of gastric residuals, and vomiting up to a full clinical picture of necrotizing enterocolitis (NEC). The longer they are kept on total parenteral nutrition, however, the higher the risks of catheter-related infections or thrombosis (3). Neonatologists are aware that human milk is preferable to standard preterm formula (SPF) in fighting feeding intolerance (4), although the former may not always be available. In this case, we speculate that an elemental, amino acid formula (AAF) may be equally tolerated by the intestine of the VLBW IUGR infant than SPF. Protein hydrolysis in preterm infant formula has been shown to accelerate gastrointestinal transit and feeding advancement (5,6). Elemental formulas may even be more beneficial given the anti-inflammatory properties demonstrated in selected gastrointestinal illnesses (7,8).
AAF has few clinical indications in neonates (eg, severe cow's milk intolerance) and its nutritional adequacy has been questioned in preterm newborns. Data on the safety and efficacy of AAF in feeding intolerant neonates are lacking.
We have conducted a prospective, pilot clinical trial in which VLBW IUGR infants with severe feeding intolerance mandating the discontinuation of enteral nutrition were rescued with AAF. Such infants were compared with controls who never developed feeding intolerance for safety of the intervention.
This pilot study included all IUGR VLBW neonates born at the neonatal intensive care unit (NICU) of the University “Federico II” of Naples between January 2006 and June 2009 for whom maternal milk was not available. Exclusion criteria were major congenital malformations and anomalies that may interfere with feeding, chromosomal abnormalities, severe sepsis, and transfer to another hospital. The present study was approved by the local ethical committee and informed consent was obtained from parents. Birth weight, gestational age, sex, type of birth, antenatal steroids, and Score for Neonatal Acute Physiology (SNAP)-II score were recorded.
According to the NICU protocol, enteral feeding (1 mL every 2 hours) was started for all of the infants on the second day of life (nutrition period 1 [NP1] in Fig. 1). Feeding with SPF (Pre Aptamil, Milupa, Friedrischsdorf, Germany) was advanced daily by 16 mL · kg−1 · day−1 to 150 mL · kg−1 · day−1. The gastric residual volume was checked before each feeding. Feedings were withheld: in cases of gastric residual volume, either 5 mL/kg or higher than the scheduled feed; when >70% of milk feeds were not tolerated in the previous 24 hours; in the presence of biliary or bloody gastric residuals; in cases of abnormal abdominal examination (defined as abdominal distension, persistent visible bowel loops, absent bowel sounds); and/or in cases of abnormal abdominal x-ray. The attending neonatologist performing the clinical evaluation was blind to the purpose of the study. As soon as the residuals, the abdominal examination, and/or x-ray returned to normal, feeding was resumed with AAF (Neocate, Nutricia Italia, Milan, Italy) at the same speed (NP2 in Fig. 1). Study endpoint was the achievement of full enteral feeding (150 mL · kg−1 · day−1) for all of the infants, whether on SPF or AAF. When the latter neonates achieved full enteral feeding, they were switched to SPF.
The primary outcome was time (days) to reach full enteral feedings. Secondary outcomes were time (days) of parenteral nutrition (central venous catheter and peripheral venous catheter), time (days) on central venous catheter (umbilical vein and percutaneous catheter), and formula tolerability based on 2 indexes similar to those used by Mihatsch et al (5) to evaluate the tolerability of an hydrolyzed formula in preterm neonates, that is, the number (%) of gastric residual volume >5 mL/kg over the total number of feedings and the mean gastric residual volume (residual/number of feedings) calculated on day 3 before and after the introduction of AAF. These indexes of formula tolerability were also used to compare cases after 72 hours on AAF (ie, NP2) versus controls (infants with a comparable gestational age ±1 week and postnatal age ±1 week).
Additional data were recorded to evaluate the possibility of undesired effects, that is, weight at 21 and 28 days of postnatal age; serum parameters for all of the infants within 3 days after the achievement of full enteral feeding when both groups were fed with SPF (pH, urea, creatinine, albumin, total proteins, total calcium, phosphorus, alkaline phosphatase); outcomes at discharge: death, broncopulmonary dysplasia, intraventricular hemorrhage >2°, periventricular leukomalacia, retinopathy of prematurity >2°, NEC >2° diagnosed according to the modified Bell criteria (9); growth at 12 months of corrected age: weight, length, and head circumference.
Infants on AAF were our case population and their data were compared with that of both neonates who were always fed with SPF and to themselves while on SPF. Parametric data are shown as mean and standard deviations and were analyzed with the Student t test; nonparametric data were analyzed with the Mann-Whitney U test and the χ2 test with Yates correction. SPSS (SPSS Inc, Chicago, IL) was used to analyze the data and a level of significance was set at P < 0.05.
From January 2006 to June 2009, 130 IUGR VLBW infants were admitted, 67 for whom no maternal milk was available. Three neonates met the exclusion criteria (2 were diagnosed as having early-onset sepsis and 1 as having esophageal atresia); therefore, 64 were enrolled in the study with 22 cases and 42 controls.
Table 1 shows the demographics of our population with no difference between groups except for the SNAP-II score, higher in the case group. This suggests that infants who later developed prominent feeding intolerance had significant worse clinical conditions at admission. AAF for cases was started at 7.52 ± 306 days of life. Table 2 summarizes the time to full enteral feeding and on parenteral nutrition. Controls, who were kept on SPF for both NP1 and NP2, show 1 figure for each outcome. For cases, NP1 (while on SPF) and NP2 (while on AAF) are reported separately. Cases had a longer NP1 + NP2 time needed to reach full enteral nutrition, duration of parenteral nutrition, and central venous access; however, NP 2 outcome times for cases were comparable with NP1 + NP2 in controls.
Table 3 shows a trend for lower gastric residual volumes in cases compared with controls that did not reach statistical significance; however, as shown in Table 4, the introduction of AAF significantly and rapidly reduced the number (%) of gastric residual volume >5 mL/kg and the mean gastric residual volume (residual/number of feedings) after AAF introduction both calculated on day 3.
No difference was recorded in weight at the postnatal age of day 21 (1245 ± 357 g for cases and 1383 ± 347 g for controls) and day 28 (1460 ± 402 g for cases and 1444 ± 345 g for controls). Similarly, Table 5 demonstrates no difference between groups in main blood parameters performed within 3 days after achieving full enteral nutrition and switching to SPF (except for total protein that was in any case within the normal range). Main outcomes at discharge and growth parameters at 12 months of corrected age were not different between groups as shown in Table 6. Once on full enteral feedings, cases were switched back to SPF (at 23.6 ± 15.6 days of life) without feeding intolerance of clinical significance.
Our results show that an elemental formula is a safe nutritional alternative when rescuing VLBW IUGR neonates with severe feeding intolerance. We also gained preliminary evidence that AAF may ameliorate the clinical picture.
The role of growth retardation as an additional factor hampering intestinal function in preterm neonates has been suggested by several authors; however, Mihatsch et al (9) showed that VLBW IUGR infants tolerated enteral feedings as well as their AGA controls. Asphyxia may play a more important role in deranging intestinal motility of the preterm infant, resulting in signs and symptoms of feeding intolerance (10). Accordingly, neonates in our population with a worse initial clinical presentation, summarized by a higher SNAP-II score, became progressively intolerant to SPF, requiring long-term parenteral nutrition. The introduction of an amino acid–based formula was followed by a rapid and significant improvement of enteral feeding indexes. When considering nutrition on AAF, its tolerability and duration were similar in cases and controls (Tables 2 and 3).
A fast achievement of full enteral feedings can be translated into substantial savings mainly in infant exposure to the risks of indwelling lines but also in human resources and cost for preparing parenteral nutrition. Pharmacologic and nutritional approaches have been launched to address this issue. Classic prokinetic drugs have been used to fight feeding intolerance (11,12) with less fortune than the antimicrobial erythromycin (13). The latter coordinates via the motilin pathway the gastric and intestinal aboral motor activity.
A hydrolyzed protein formula (HPF) has also been shown to accelerate early feeding advancement in VLBW infants (14). Tormo et al (15) showed that HPF induced higher motilin level than intact protein formula. Also, protein hydrolysis may accelerate gastrointestinal transit via a reduced B-casomorphin activity (16).
Given the paucity of data on the topic, it is not known whether AAF can benefit the feeding intolerant VLBW neonate via the same mechanisms. Because elemental diets are in use for inflammatory bowel diseases (ie, cow's milk protein intolerance, Crohn disease), a speculation is that AAF may mitigate the gut inflammation of a neonate with severe, pre-NEC, feeding intolerance (7,8,17). Interestingly, macrolides have been found to downplay intestinal inflammation in an experimental colitis model in the rat (18). Also, unlike AAF, a significant amount of ingested protein from SPF may escape absorption in the lumen of the small gut and reach the colon, where an increased protein putrefaction by the microbial flora may impair feeding tolerance. If proven, these mechanisms may offset the higher osmolality of the AAF, which, although well within the limits regarded as safe by the American Academy of Pediatrics, is thought to hamper rather than facilitate feeding progression (19).
Both AAF and HPF can be questioned for the long-term nutritional adequacy in extremely preterm neonates. In 1995, Rigo et al (20) showed that HPF were not equivalent to whole-protein formulas in terms of nutritional efficiency for both preterm and term infants, and more recently, concerns arose from the use of HPF as a first-line nutrition for an average of 3 weeks in a general population of VLBW infants (21,22). Unlike these studies, our intervention focused on a select group of patients and a much shorter rescue trial. AAF, while improving enteral feeding, caused no significant difference in routine laboratory work at the time full enteral feeding was reached and cases were switched back to SPF; also, both short- and long-term growth were not impaired, although we cannot exclude that subclinical nutritional differences of individual nutrients between groups may have occurred. In conclusion, this pilot study showed that a short course on AAF is safe and associated with improvement in feeding tolerance in VLBW IUGR infants; however, a randomized trial is required to show whether AAF improves feeding tolerance in contrast to SPF in such neonates if human milk is not available. Such studies are highly warranted, because new protein hydrolyzed formulas are targeted to the needs of the preterm neonate (23) and severe feeding intolerance remains a constant life threat for VLBW infants.
The authors thank Dr Luis Pereira da Silva for expert advice and helpful suggestions. We are also indebted to Dr Roberto Paludetto for constant supervision of the NICU clinical activity while the study was ongoing. We acknowledge the help of Mrs Shannon and Mr Charles Worthy, who carefully reviewed the manuscript.
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