Systematic review of the impact of feed protein type and degree of hydrolysis on gastric emptying in children

To the best knowledge of the authors this is the first systematic review aiming to assess the impact on GE in paediatrics of both the type of protein and level of hydrolysis in paediatric feeds and considers GE of breast milk as well. Our findings with regard to protein type concur with those of Woodley et al. in 2008, but add further information on GE and level of hydrolysis [9]. This review identified 8 paediatric studies using current validated methods of scintigraphy or 13C-OABT in both healthy children, those with neuro-disabilities and reflux.

We identified 2 studies that found increased GE with breast milk versus whole protein formula milk. The study by Van Den Driessche et al. [20], however, did have significant differences in age between the two studied groups, which could have affected the result. Billeaud et al. [11] compared the GE of breast milk to five other feeds, including a predominant whole whey formula and two predominant casein feeds. In all aforementioned feeds, GE was slower in the whole protein feeds than in breast milk. Although only 2 studies with a total of 230 infants on either breast milk or a variety of infant feeds were suitable for inclusion, the results seem to indicate that breast milk empties faster than whole milk formulas. The superior emptying properties of breast milk, seemed to be maintained even with increasing volumes, according to a study by Pozler et al. [26]. Conceptually this superior GE pattern with breast milk can be explained due to its high whey content with faster GE properties, unique fat blend, lower osmolality than whole formula milk, and most importantly non-nutritive factors, including amylase, that may aid digestion and gastric emptying [27‐29].

In nutritional practice it is often recommended to use whey protein for better GE in children with disorders that affect motility of the gastrointestinal tract. The purported benefits of whey protein relate to the predominance of β-lactoglobulin, which remains soluble in the stomach, therefore transiting more rapidly to the upper jejunum [29]. In the past there have been concerns also that casein dominant feeds cause lactobezoars due to slower gastric emptying in preterm infants [23]. In our systematic review we found 5 studies, that each included between 10–20 children, investigating GE of predominant whole casein versus whey protein feeds [7, 11, 22, 23, 30]. In none of these studies 100 % casein feeds were compared to 100 % whey feeds, but instead comparisons of predominant whole casein feeds to whole protein feeds containing either 50 % or 60 % whole whey. In 4 studies, the predominant whole whey feeds emptied faster than the predominant casein feeds, however Thorkelsson et al. [23] found no difference in GE between predominant whole casein or whey feeds. The opposing outcome of the studies could be explained by differences in feed composition but also by the difference in study population. Those studies that found a difference in GE between type of protein occurred in children that either had GOR or CP, with GOR also being prevalent in the latter cohort [31]. Predominant whole whey protein therefore may have a faster GE in children that have underlying GOR, but not healthy children. Further studies are required to answer this question and should implement the method from Brun et al. [7] matching volume, carbohydrates, fats, energy and only varying protein content. To date no paediatric study has compared GE of 100 % whole whey and 100 % whole casein feeds, likely due to the unavailability of commercially prepared 100 % casein based formula. Currently only mixes of whey and casein have been used suggesting that a predominant whey feed (that also contains casein) may have better GE properties in GOR (Table 3).

On the question of the impact on hydrolysis 5 studies looked at the effect on GE. Although the study by Savage et al. [22] did find different GE pattern between pHF whey and whole protein feeds, it was only the combined data of whole predominant whey and pHF whey that yielded a statistically significant result and did therefore not add further data to the question at hand. Staelens et al. [24] found that a 100 % eHF whey emptied faster than both pHF whey and whole protein feed in healthy infants. Billeaud et al. [10] also found that in infants with/without GOR the hydrolysed whey emptied faster at 120 min than all other whole protein formulas. Brun et al. [7] on the other hand found that hydrolysed whey protein emptied slower than a mix of 60:40 whole whey and casein feed and also an amino acid formula in children with CP. Similarly, Tolia et al. [25] also found that in children with GOR, the whey hydrolysate had a significantly slower GE when compared to the whole whey casein mixed feed. The findings seem to contradict each other and may be explained by the different study populations (healthy versus CP/GOR), the age (infants versus older children) and also by feeds that were not optimally matched. Most importantly the level of hydrolysis was not specified in 3 of the studies and Staelens et al. [24] clearly showed a difference between pHF and eHF whey in GE. In addition there are significant differences in feed composition in some of the studies. It is therefore difficult to draw any firm conclusion on the question of GE between whole and hydrolysed protein (Table 3).

The limitations of this review include the very small number of publications that have been published using either scintigraphy or 13C-OABT as methods for GE. Although these methods have been validated, it is important to be aware of their limitations. The most pervasive pitfall in GE by scintigraphy is the use of short-duration detailed studies, lasting 2 h, and extrapolating the t1/2 or the proportion emptied at 4 h using a power exponential analysis. For the 13C-OABT, pitfalls include potential loss of accuracy in patients with other diseases involving the intestinal mucosa, pancreas, liver, and respiratory system. On the other hand C13 octanoic acid is absorbed across the mucosa undigested, so it is not dependent on biliary and pancreatic secretions or mucosal enzymes [32]. Other methods for gastric empting in children have been used such as imaging tests (i.e. magnetic resonance imaging, functional ultrasonography) and imaging procedures, which have had good results; however, the ability to ensure consistency between the studies using this method is less reliable and often require skilled technicians [13, 32, 33]. Therefore, although other proxy methods for gastric emptying in children exist, it would have made any comparisons difficult due to the difference in measurement techniques and varying reliability. Further limitations of this systematic review which reduces its ability to draw firm conclusions, are the small sample sizes in the majority of studies, the varying feed composition (i.e. varying fat and osmolality), level of hydrolysis, volume consumption and different patient cohorts (healthy versus unwell) that these feeds have been tested in including preterm infants that have different GE to full term infants [6, 34‐36]. The majority of the aforementioned limitations have also been highlighted by a previous review by Woodley et al. [9] and have not been optimally addressed by subsequent studies.