What Is Known
- Feeding intolerance is a common clinical issue in the care of premature infants.
- The factors accounting for this issue are presently unknown.
- Current enteral feeding protocols recommend starting at low volumes and progressing slowly after checking for gastric residuals.
What Is New
- The gastric emptying rate of preterm infants is content volume-dependent.
- The gastric emptying rate of preterm infants is independent of postnatal age.
Amongst the many therapeutic challenges involved in the care of premature infants, the provision of adequate enteral nutrition is one the most complex. At the time of enteral feeding initiation, many of these infants exhibit gastric residual resulting in slow milk volume advancement and prolonged dependence on parenteral nutrition (1). The factors accounting for the presence of gastric residuals in otherwise healthy preterm neonates are unclear. Their identification is of importance, however, as parenteral nutrition is associated with increased infection rates, liver dysfunction, and prolonged hospital stay (2).
Whether a failure to completely clear the gavage milk is a manifestation of feeding intolerance, or reflective of a reduced gastric emptying rate is presently unknown. There are limited data regarding the preterm infants’ regulation of gastric content emptying. Factors such as the type of milk utilized (3), milk fortification (4), osmolarity (5), formula composition (6–8), and body position (9,10) have been shown to impact on the preterm infants’ gastric emptying rate. There are also data suggesting that the newborn gastric emptying rate is not constant and highest in the immediate period following feed administration (11). Whether this relates to the fact that the stomach content is higher immediately after the milk is administered is unclear, yet, gastric emptying time in adults is dependent on the meal volume (12,13).
Hypothesizing that early in life, the gastric emptying rate is directly proportional to the gavage milk volume, we conducted a single unit, observational prospective study of premature neonates during the first month of life.
This study was approved by the Hospital das Clínicas of Ribeirão Preto (HCRP), University of São Paulo Research Ethics Board (Protocol # 16621/2014).
Following parental consent, 25 infants with a gestational age between 28 and 32 complete weeks admitted to HCRP neonatal intensive and intermediary care units from January through December 2015, were enrolled. The enrollment criteria included gavage enteral feeding and ultrasound equipment availability. The exclusion criteria included congenital malformations, surgical abdominal conditions, and hemodynamic instability requiring inotropic and/or vasopressor support anytime during the first month of life. Infants reported to have gastric residual, or considered by the clinical staff as having feeding intolerance were excluded. Attempt was made to enroll each infant during their first week of life. Enrolled infants who remained at HCRP nurseries were evaluated weekly until transferred to another hospital, or reached an age older than 4 weeks.
Institutional Enteral Feeding Regimen
During the study period, infants were nasogastrically fed starting on the first day of life. Given the higher cytomegalovirus prevalence in pregnant women in Ribeirao Preto (14), raw milk from the infant's own mother is not used for neonates below 32 weeks of age during the first weeks of life. As such, all enrolled infants were gavage fed, by gravity or pump, pasteurized donor breastmilk.
The institutional feeding guidelines recommend advancement of the enteral intake at the rate of 20 ml · kg−1 · day−1 up to a maximum of 180 ml · kg−1 · day−1 . The recommended frequency of gavage feeding frequency was every 2 or 3 h. Donor breastmilk was fortified with a multicomponent fortifier (FM85, Nestlé, São Paulo, Brazil) at a dose of 5 g/100 ml when the total enteral intake reached 100 ml · kg−1 · day−1.
Gastric residuals were checked before each feeding. The residuals were considered acceptable for continuation or enteral intake, if nonbilious in nature and equal, or less than 30% of the previous feed volume in the absence of vomiting and abdominal distention, or discoloration. The investigators had no input on their prescribed enteral regimen.
The studies were conducted with the infant lying supine in an incubator, or radiant warmer. All gastric ultrasound images were obtained by one of the investigators (C.H.F.F.) with the Philips HD11 XE Ultrasound System (Philips Medical Instruments Bothell, WA), using a microconvex 8 to 5 MHz transducer. To obtain the measurements, the milk-filled stomach was located, and the laterolateral, anteroposterior, and longitudinal axis dimensions were recorded in triplicates. The following, previously validated (15), equation for preterm neonates was used to calculate the gastric content volume: laterolateral × longitudinal × anteroposterior × 0.52.
The gastric content volume was measured 3 times as follows: immediately before, to evaluate the residual volume; 30 minutes; and 60 minutes after the gavage feed ended. The gastric content emptying rate at 30 minutes was estimated as the difference between the initial gastric content (gavage fed + prefeed gastric residual volumes) and the second ultrasound volume obtained 30 minutes postfeed over the time period between the measurements. The emptying rate at 60 minutes was obtained 60 minutes after the gavage feed ended and calculated from the 30- and 60-minute ultrasound gastric volume measurements. Gastric content emptying rate was expressed as ml · kg−1 · hour−1. The study protocol, showing the average times in minutes for the gavage feeding duration, is displayed in the Supplemental Figure (Supplemental Digital Content 1, https://links.lww.com/MPG/B341).
Data were first screened to determine whether it fitted a normal distribution. Parametric testing was utilized for statistical analysis. When employing ANOVA, multiple comparisons were obtained by the Tukey-Kramer testing. Data are presented as mean ± SE.
Twenty-five infants with a birth weight of 1.32 ± 0.03 kg, gestational age of 29.5 ± 0.1 weeks were evaluated during the first 4 weeks of age. Five of the 25 subjects were identified as small for gestational age by the Fenton reference growth curve (16) and the sex breakdown was 12 female and 13 male infants. The total fluid intake over the first 4 weeks of life for these infants is shown in Figure 1.
Seventy gastric content volume assessments each were obtained at 30- and 60-minute postfeed for a total of 134 ultrasound measurements. Out of the 25 subjects, repeated ultrasound assessments at different postnatal ages was available for 18 infants. The Table 1 depicts the demographic characteristics of the study population and the number of ultrasound assessments at each postnatal age period.
Figure 2 illustrates the gastric emptying rate and corresponding initial stomach content volume for each of the 2 30-minute epochs across postnatal ages. As expected, the gastric volume measurements were higher for the first interval, when compared with the second 30-minute epoch post-feed (P < 0.01).
For the first 30-minute epoch, the feed volume for each postnatal age in weeks increased at the same proportion as the gastric emptying rate and the latter was significantly higher at 3 and 4 weeks of age, when compared with the 1-week measurements (Fig. 2A; P < 0.01). No postnatal age difference in gastric emptying rate was present for the second 30-minute epoch (Fig. 2B). These findings are highly suggestive of a causal relationship between these parameters such that the rate of gastric emptying depended on the stomach content volume.
To investigate the gastric content volume and emptying rate relationship, we plotted the linear regression between these variables including all ultrasound measurements from both 30 minute epochs. As shown in Figure 3A, there a strong correlation between the gastric content volume and emptying rate was observed (R2 = 0.65; P < 0.01).
As a further attempt to evaluate the relationship between the stomach content volume and related gastric emptying rate, we combined the 30 and 60 minute postfeed measurements. Figure 3B illustrates the postnatal age-specific gastric emptying rate for stomach content volumes in 5 ml/kg increments. For all postnatal ages, the gastric emptying rate was directly proportional to its content and a greater than 6-fold increase was observed for this parameter, whenever comparing the lowest and highest gastric volume strata (P < 0.01).
Lastly, we comparatively evaluated 28 and 30 weeks gestation infants’ 30-minute postfeed gastric emptying time and volume, as well as the total enteral intake. As shown in the Supplementary Table (Supplemental Digital Content 2, https://links.lww.com/MPG/B342), when normalized to body weight, there was no gestation-dependent difference for any of the parameters.
In this study, we showed that the stomach content volume is the main determinant of the gastric emptying rate in preterm neonates. For 28- to 32-week gestation infants, the higher the postfeed stomach content volume, the greater is the rate of gastric emptying, independently of postnatal and gestational age.
Gastric residual is commonly present during the early stages of enteral feeding progression in preterm infants. These are often interpreted as indicative of feeding intolerance resulting in slow enteral feed advancement, thus prolonging the need for parenteral nutrition (17) and leading to a longer hospital stay (18). Data from the Canadian Neonatal Network indicate that for subjects requiring intensive care, an average of 44 days of parenteral nutrition was required by preterm neonates free of gastrointestinal disease, as compared with only 6 days for term infants (19).
In adult subjects, gastric emptying time is directly proportional to the meal volume (12,13). There is reason to believe that a similar relationship is present early in life. Previous studies involving preterm neonates reported on data suggesting that protocols calling for initiation of enteral feeds with higher, as compared with low volumes, resulted in shorter time to reach full enteral nutrition (20–22). Yet, none of these studies evaluated the correlation between stomach content volume and emptying rate. To the best of our knowledge, this is the first study demonstrating that for preterm neonates, the gastric emptying rate is content volume-dependent.
The present study findings have important implications to the current feeding advancement protocols for preterm infants. Mostly because of the limited evidence that rapid advancement of enteral nutrition predisposes preterm infants to develop necrotizing enterocolitis, the current protocols recommend initiation of feeds with small milk volumes and slow advancement of the enteral intake (18,23,24). As shown in the present study, such strategy favors reduced gastric emptying rates and the presence of gastric residuals at the initiation of feeds.
To overcome the impact of the presence of gastric residual at the initiation of enteral feeds, some authorities have recommended either not checking (25), or avoiding the interpretation of feeding intolerance until the residual volume is equal/greater than 50% of the feed volume (17). Enteral feed protocol strategies like this may prove successful, not because the residual volume is ignored, but because of the fact that it allows for earlier attainment of feed volumes large enough to enhance gastric emptying and thus feeding tolerance.
This study does have limitations that need to be addressed. Firstly, the study was an observational one enrolling only infants deemed to be clinically stable and tolerating enteral feeds. Ideally, an evaluation of the individual gastric emptying rate at different feed volumes would have provided conclusive data regarding the correlation between these 2 variables. Yet, such a research protocol was deemed a “high risk proposal” by the local research ethics board.
Instead, we took advantage of the fact that in spite of the existence of an institutional feeding protocol, there was a great variability in the feed frequency, rate of milk volume advancement, and total enteric intake in the study population (Fig. 1). This was unrelated to individual subject feeding tolerance as all infants presenting signs such as the presence of large gastric residuals, or abdominal distention were excluded. Such variability allowed us to compare gastric emptying rates at different stomach content volumes for each postnatal age.
In conclusion, we showed novel evidence that the gastric emptying rate of preterm neonates is directly proportional to the stomach content volume. Further studies addressing the potential improvement in preterm infants’ feeding tolerance by allowing larger than currently recommended feed volumes at the initiation of enteral nutrition, are warranted.
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