Optimizing enteral nutrition is a major challenge in very-low-birth-weight (VLBW) infants. Most clinicians follow a conservative approach in initiation and advancement of enteral feeds in these infants because of possible risk of feed intolerance or necrotizing enterocolitis (NEC). Early initiation of minimal enteral feeds has been shown to improve feed tolerance, reduce days to full enteral feeds, shorten duration of parenteral nutrition, and hospital stay (1,2). Up to two-thirds of VLBW infants have been reported to experience feed intolerance (3–5). Traditionally, volume and nature of prefeed gastric aspirates have been used to define feed intolerance; however, there is no unanimity for its definition. It is unclear whether prefeed aspirates are a benign consequence of delayed gut maturation and motility, or they are associated with subsequent development of NEC (5). In extremely preterm infants prefeed gastric residues up to 3 mL may be inconsequential and even greenish aspirates may be physiological (6). Routine measurement of prefeed aspirates may result in delay in initiation or advancement of enteral feeds. Prefeed abdominal circumference (AC) measurement has been suggested as an alternative to gastric aspirates for the assessment of feed intolerance (7). The utility of AC in clinical practice has, however, not been evaluated systematically. We performed this study to evaluate the usefulness of AC measurement as an indicator of feed intolerance as compared with prefeed gastric residual measurement.
Design, Setting, and Population
The present randomized control trial was conducted in neonatal intensive care unit of a tertiary care hospital in northern India, between December 2007 and April 2009. All infants with birth weight <1500 g (VLBW) admitted to neonatal intensive care unit were screened. Infants with major congenital abnormalities, gestation <27 or >34 weeks, absent or reversed end-diastolic flow, or Apgar score <3 at 5 minutes were excluded. A written informed consent was obtained from the parents. The study protocol was approved by the institutional review board and ethics committee.
A computer-generated block randomization sequence with block size of 4 was prepared by a person not involved in the clinical care, measurement of outcomes, or analysis of data. This sequence was kept in sequentially numbered sealed opaque envelopes. At the time of initiation of first feed the eligible subjects were randomized to 2 groups—this was based on the measure of feed intolerance—AC group or gastric residual volume (GRV) group. The attending neonatologist allocated and assigned the infants to intervention. Blinding was not possible in our study.
All of the enrolled VLBW infants received parenteral nutrition (PN) as per the unit protocol to achieve a calorie intake of 60 to 90 kcal · kg−1 · day−1. They were assessed daily for feed initiation. Once infants were hemodynamically stable with soft abdomen and audible bowel sounds, gavage feeds were initiated as intermittent boluses for 10 to 15 minutes, at 2-hourly intervals. Feed was started at 10 mL/kg in infants <1250 g and 20 mL/kg in infants ≥1250 g. Subsequent advancements were made by 20 mL · kg−1 · day−1 as tolerated, to a maximum volume of 180 mL · kg−1 · day−1. Expressed mother's milk was preferred; if not available, standard preterm formula with a calorie content of 80 kcal/100 mL was used. Human milk fortifier was added once infant tolerated 100 mL · kg−1 · day−1 feed volume, to make calorie content of 80 kcal/100 mL. PN was discontinued once 100 mL · kg−1 · day−1 of feeds were achieved.
In AC group, AC measurements were performed before each feed using a standard, disposable nonstretchable paper tape with minimum markings of 1 mm. The tape was positioned 1 cm above the umbilicus and was read along its bottom edge. A mark was made along the lower edge as reference for subsequent measurements. An increase in prefeed AC by ≥2 cm from baseline was considered as a sign of feed intolerance. In AC group, gastric residues were not routinely performed unless the AC increased by >2 cm. The decision for feed interruption was merely based on an increase in abdominal girth. Least AC measurement during the previous 24 hours was used as the baseline reference.
Feed intolerance in GRV group was defined as presence of either 1 or more of following features: bilious/hemorrhagic aspirates or volume of aspirates >50% of previous feed or >3 mL, whichever was larger. If the gastric residues were between 30% and 50% of the previous feeds, the same volume was continued without making daily increment. The gastric residues aspirated were discarded. The feeds were advanced as per protocol if gastric residues were <30% of previous feeds. Infants in both the groups, who experienced feed intolerance, were kept nil per os (NPO) for next 24 hours and PN was continued. Regurgitation of feeds or nonbilious vomiting were not considered as feed intolerance unless they were associated with an increase in AC of >2 cm or large or abnormal prefeed gastric aspirates in respective groups. In infants with feed intolerance, readiness for re-initiation of feeds was assessed every 24 hours. Once AC was less than or equal to baseline (AC group) or gastric aspirates were clear and <10 mL · kg−1 · day−1 (GRV group), feeds were restarted at 50% of the volume being delivered at the time of feed interruption. Infants were evaluated for electrolyte imbalance, sepsis, NEC, and managed as per unit guidelines. The feeds were also withheld for hemodynamic instability, abnormal abdominal signs such as abdominal wall discoloration and tenderness, recurrent apnea requiring continuous positive airway pressure, or persistent seizures. These infants were restarted on feeds after 24 hours, once they became hemodynamically stable without need for inotropic support.
During the designing phase of study, 8 staff nurses were trained to standardize the technique of AC and GRV measurements. Agreement within and between observers was assessed on a sample of 20 paired observations for each assessor with principal investigator as the reference. On reliability analysis, there was a good intraobserver and interobserver agreement among the assessors with intraclass correlation coefficient ranging between 0.93 and 0.98.
The primary outcome in our study was time taken to achieve full feeds (180 mL · kg−1 · day−1), which were tolerated for at least 24 hours. Secondary outcome measures included incidence of feed intolerance; days taken to regain birth weight defined as day of life on which baby reached or crossed birth weight and maintained it for 3 days; feed interruption days, cumulative days on PN; incidence of NEC (Bell stage ≥2); incidence of culture positive sepsis; duration of hospital stay; and mortality.
Sample Size and Statistical Analysis
Sample size was calculated based on our pilot observation. For an expected difference of 3 days (SD 4.1 days) in time to reach full enteral feeds, 40 subjects were required in each group, for a power of 90% and a significance level of 0.05. The statistical computations were performed using SPSS for Windows, version 17.0 (SPSS Inc, Chicago, IL). Continuous variables were compared using t test or Mann-Whitney U test as per the distribution of data; categorical variable were compared using χ2 test. Kaplan-Meier survival analysis was performed to assess time to event variables. To assess the effect of other confounding factors on our primary outcome, univariate, and multivariate analyses were performed using the Cox proportional hazards regression model.
Of 144 VLBW infants admitted during study period, 80 were randomized (Fig. 1). Maternal and neonatal characteristics of study subjects are depicted in Table 1. The mean (SD) birth weight and gestational age were 1220 (76) g and 30.4 (1.6) weeks, respectively, in AC group and 1210 (183) g and 30.3 (1.5) weeks, respectively, in GRV group. Median age at feed initiation was comparable in 2 groups. The outcome measures of study participants are displayed in Table 2. On survival analysis, the median (interquartile range) time to reach full feed was 10 (9–13) and 14 (12–17.5) days in AC and GRV groups, respectively (P < 0.001) (hazard ratio 1.91 [1.19–3.05], [P = 0.01]) (Fig. 2). The hazard ratios of possible confounding factors affecting time to reach full feeds in the 2 groups are depicted in Table 3. Infants in AC group had higher chance of reaching full feeds compared with GRV group (adjusted hazard ratio 2.78, 95% confidence interval 1.63–4.75, P < 0.01). A significantly higher number of infants in GRV group experienced feed intolerance as compared with AC group, 80% versus 35% (P < 0.001). Overall, NPO days and duration of PN were significantly less in AC group as compared with GRV group. The NPO days owing to reasons other than feed intolerance were not statistically significant in the 2 groups (Table 1). The incidence of culture-positive sepsis was 17% and 30% in AC and GRV groups, respectively (P = 0.18). There was no significant difference in mortality in the 2 groups. Three infants in each group expired before reaching full feeds; of these, 5 died because of Gram-negative sepsis and 1 because of NEC.
Enteral nutrition remains a challenging task in VLBW infants. Early initiation and rapid advancement of feeds have been attempted to reduce the time to full enteral feeds (8). Feed intolerance and interruption is a major problem in VLBW infants because of gut immaturity and other comorbid factors. Traditionally, the volume or color of prefeed gastric residues has been used as a criterion to define feed intolerance (9,10). This strategy, however, has its own fallacies as in extremely preterm infants prefeed gastric residues up to 3 mL may be inconsequential and even greenish aspirates may be physiological (6). The volume of gastric residues has also been reported to vary with the position of the baby, location of orogastric tube, and the technique of extraction (11,12). AC measurement has been used as an alternate tool to define feed intolerance but has not been evaluated systematically.
We assessed the usefulness of prefeed AC as a measure of feed intolerance. The infants in AC group experienced fewer feed interruptions and reached full feeds 4 days earlier than those in GRV group even after adjusting for the confounding factors. The number of feed interruption days and duration of PN were also significantly less in AC group. PN has been reported to be associated with increased risk of nosocomial sepsis in infants (13–15). Any strategy that leads to a significant reduction in sepsis is likely to improve neonatal outcomes, especially in resource-limited settings in which the burden of nosocomial infections is high. We evaluated the possible clinical benefits of reduced PN days in our study. The incidence of culture positive sepsis in GRV and AC groups was 30% versus 17%. This difference was statistically not significant, possibly owing to small number of subjects in our study. To draw a conclusive inference for observed reduction in sepsis, we would have required 166 infants in each group.
The safety and efficacy of any intervention for feeding in VLBW infants cannot be ascertained without assessing the risk of morbidities such as NEC. There are conflicting reports regarding the relation between prefeed gastric residues and subsequent development of NEC (16,17). Bertino et al (16) in a retrospective study reported that as compared with the control group, the infants with NEC had higher gastric residues (40% vs 14%) during 6 days before its onset. In a similar study, the maximum gastric residues as percentage of the previous feed in infants with or without NEC were 113.24% and 42.87%, respectively (17). This wide variability makes gastric residues an unreliable predictor of NEC. The present study is not adequately powered to comment on this complication, and this needs to be further evaluated in larger studies.
The relation between prefeed AC and GRV is not clear. Malhotra et al (7) reported that in preterm infants with an increase in AC by 2 cm or more, the GRVs were at least 23% of the previous feed. We observed that in the AC group, if there was an increase in AC by >2 cm, the GRV was at least 40% of the previous feed (median [interquartile range] 80 [53.5–183]). We used an increase in AC by 2 cm or more above the baseline as a cutoff to define feed intolerance. This was based on preliminary observation by Bhatia et al (18) who reported that in preterm infants on total enteral feeds, the variability of AC was up to 1.8 cm in 95% of the observations. Further studies are required to know whether a uniform threshold of an increase in AC is appropriate for infants across all gestations.
Our study highlights that compared with gastric residues, prefeed AC measurement as a criterion for feed intolerance resulted in early achievement of full feeds and lesser feed interruptions. If we had used AC monitoring in all of the subjects, we could have reduced the feed interruptions by approximately half. These findings suggest that AC measurement may be used as a preferred tool to monitor feed intolerance. The limitation of this study was that we could not evaluate the impact of this strategy on incidence of NEC owing to small number of subjects. Also, the utility of this strategy needs to be confirmed in extremely premature and extremely-low-birth-weight infants.
Feed intolerance is a common occurrence in VLBW infants. Our study suggests that AC monitoring is a better marker of feed intolerance than prefeed gastric residual monitoring. The use of AC monitoring as a measure of feed intolerance may result in earlier achievement of full feeds and lesser feed interruption days.
We are grateful to Anil Batra, Naveen Gupta, Anup Jalan, and neonatal staff who helped in assessing patients during the study. We are also thankful to Ms Parul, biostatistician, Sir Ganga Ram Hospital, New Delhi, for help with statistical analysis.
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Keywords:© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
abdominal circumference; feed intolerance; gastric residues