The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent: a longitudinal observational study

Introducing preterm infants to enteral feeding is challenging. Gastrointestinal (GI) motility of preterm infants is limited causing delay in gastric emptying and intestinal transit. This in turn could easily result in intolerance to feeding [1]. Enteral feeding has beneficial effects on the structural and functional development of the GI tract [1, 2]. The passage of enteral feeds leads to an increased metabolic demand on the small intestine. This results in increased intestinal perfusion from the superior mesenteric artery (SMA) known as postprandial hyperaemia [3, 4]. If this increased metabolic demand after enteral feeding cannot be met, feeding intolerance (FI) may occur, resulting in delayed full enteral feeding (FEF) and possibly even necrotizing enterocolitis (NEC) [5‐8]. Furthermore, as preterm infants are at risk of impaired cerebrovascular autoregulation, postprandial redistribution of blood in favour of the intestines may result in cerebral underperfusion [9‐11].

Near-infrared spectroscopy (NIRS) is a non-invasive method to assess end-organ perfusion in preterm infants [8, 12‐14]. It allows us to measure regional tissue oxygen saturation (rSO₂) continuously [12‐14]. From this measure fractional tissue oxygen extraction (FTOE) can be calculated, which reflects the balance between oxygen delivery and consumption [12‐14].

Recent studies on NIRS or Doppler flow measurements of the SMA reported that healthy preterm infants, who tolerate enteral feeding of at least 100 mL/kg/day, demonstrate increased intestinal postprandial perfusion while cerebral perfusion remains stable [2, 15‐17]. Nevertheless, little is known about whether this capability of the premature intestine to increase its perfusion after feeding is dependent on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. In addition, it remains unclear if cerebral perfusion also remains stable when postprandial redistribution of blood in favour of the intestines occurs soon after birth or in younger infants. Furthermore, studies that evaluated whether the presence or absence of postprandial intestinal hyperaemia is associated with the development of FI or with the development of NEC, are limited. Therefore our aim was to determine the effect of enteral bolus feeding on intestinal oxygen saturation (r_intSO₂) and extraction in preterm infants during the first five weeks after birth, and to evaluate whether this effect depended on PNA, PMA, and/or feeding volumes. Furthermore, we explored whether the cerebral oxygen saturation (r_cSO₂) and extraction changed when postprandial r_intSO₂ increased after enteral feeding.

We demonstrated that in our group of preterm infants, born after approximately 28 weeks of gestation, a postprandial increase of intestinal oxygen saturation does occur, albeit at group level only in the fifth week after birth or in infants of a relatively older corrected gestational age. Furthermore, we showed that not a postprandial increase of intestinal oxygenation, but rather the absence thereof, was associated with a higher risk of a decrease of the cerebral oxygen saturation.

Our results suggest that during the first four weeks after birth at group level, intestinal perfusion does not exceed any potential increased oxygen consumption after enteral feeding. In the fifth week after birth the PMA of the remaining infants was 31.7 weeks. We assume that during this period the postprandial effect of feeding on the intestinal rSO₂ can be explained by an increasing PMA rather than PNA, because we demonstrated that infants with a PMA ≥ 32 weeks have an increased postprandial r_intSO₂. In addition, by this time the remaining infants received relatively greater feeding volumes, which we demonstrated to be another important factor to elicit postprandial hyperaemia. Previous reports showed increased postprandial intestinal oxygen saturation using NIRS [2, 15, 16] or increased postprandial blood flow velocity of the SMA using Doppler measurements [3, 4], but these measurements were mainly done cross-sectionally, in fullterm and preterm infants with a corrected GA of at least 32 weeks, and were not assessed from birth onwards.

We offer several explanations for the fact that we did not find increased intestinal oxygen saturation after enteral bolus feeding during the first four weeks after birth and in the younger infants with a PMA < 32 weeks based on the principle that intestinal oxygenation consists of a balance between oxygen supply and consumption [15]. First, it may be that neither intestinal oxygen supply nor oxygen consumption changes in very preterm infants after enteral feeding because of intestinal immaturity on account of the fact that intestinal maturation is an ongoing process up to 33 to 34 weeks of gestation, and even beyond [27].

Besides intestinal immaturity, the low feeding volumes received during the first weeks after birth, especially in the youngest infants, may only result in a limited increase of intestinal metabolism and perfusion. Previous reports on animal models demonstrated a dose-dependent hyperaemic intestinal response after feeding [28, 29]. In addition, previous studies that reported increased intestinal perfusion after feeding were performed in preterm infants who tolerated feeding volumes of 100 mL/kg/day [2, 15‐17]. We confirmed that indeed increased feeding volumes were associated with a higher chance of increasing intestinal saturation after feeding.

Another, but perhaps less likely explanation for not finding any change in intestinal oxygenation after feeding in the youngest infants, may come from a potentially perfect balance between oxygen supply and oxygen consumption. It may be that both increase equally after enteral feeding. One would, however, sooner expect such perfect harmony in the more mature infants.

Finally, several perinatal conditions may have influenced our findings. In comparison to populations reported on previously, our study population consisted of a relatively large proportion of infants who had a hemodynamically significant PDA. It has been demonstrated that preterm infants with large PDAs show a very slight increase of SMA blood flow velocities one hour after enteral bolus feeding compared to preterm infants without a PDA or a small or moderate PDA [30]. Therefore, in our study, the relative large proportion of infants with a PDA might have contributed to a lack of postprandial r_intSO₂ increase at group level. Additionally, other perinatal morbidities, (that is being born small for gestational age or anaemia, Table 1) may also have contributed to our results. Two recent studies demonstrated a lack of increase, or even a decrease, in postprandial r_intSO₂ in a group of anaemic preterm infants and in preterm infants who showed fetal signs of intrauterine growth restriction [31, 32]. Martini et al. showed that preterm infants with abnormal prenatal umbilical Doppler measurements lack any effect of the first enteral feeding on r_intSO₂ [29]. The results of these studies suggest that the intestinal response to enteral feeds is complex and that it is influenced by intestinal immaturity as well as intestinal condition and other perinatal factors [31, 32]. The hemoglobin levels in our study population decreased over time during the five weeks after birth, while we demonstrated that the r_intSO₂ increased after enteral feeding in the fifth week after birth. We therefore speculate that the maturing process of the intestine after birth and the greater feeding volumes have a larger contribution on the change in intestinal oxygen saturation after enteral feeding and attenuate the effect of the level of hemoglobin. Unfortunately, we were unable to perform subanalyses to address these issues on account of the size of our sample.

We did not observe an association between postprandially increased intestinal oxygen saturation and postprandially decreased cerebral oxygen saturation. On the contrary, we did find an association between a lack of a postprandial increase of the intestinal rSO₂ and the risk of a decreased cerebral rSO₂. We hypothesize that the infants with a lower PMA, who more often seemed to lack an adequate intestinal response, might have a less adequate cerebrovascular autoregulation and thus are at risk of compromised cerebral perfusion. A decrease of the cerebral oxygen saturation might indicate a decreased systemic circulation. One of the reasons for a decreased systemic circulation might be a lower cardiac output, but this might also be due to changes in blood pressure or redistribution of blood flow to other vital organs that temporarily have an increased metabolic demand. As the cerebral oxygen saturation is not a measure for cardiac output, assumptions concerning a decrease in cardiac output, or to what extent the cardiac output might have changed, cannot be made. Previously, stable cerebral oxygen saturation values were reported in studies that evaluated the effect of enteral feeding on rSO₂ in preterm infants [2, 16, 33, 34]. Combining these results with our results suggests that cerebral saturation is not compromised when intestinal perfusion increases after enteral bolus feeding, possibly on account of adequate cerebrovascular autoregulation, but that this may be age-dependent.

In our study, only a few infants developed NEC. The infants who subsequently developed NEC tended to have a decreasing intestinal oxygen saturation 30–60 min after bolus feeding during the first two postnatal weeks, whereas infants without GI complications, FI, and SIP did not. As a result of the very small number of infants, these results have to be carefully interpreted, and conclusions cannot be made based on these results, which require further investigation in a larger cohort.

An important strength of this exploratory study is the longitudinal design that created the opportunity to address the age-dependent component on the effect of enteral feeding on intestinal perfusion. Nevertheless, we also recognise several limitations to our study. The first limitation was the relative small population studied. Therefore we could not analyse the influence of comorbidities on intestinal perfusion after enteral feeding. Neither could we stratify the study cohort on the basis of feeding intervals or feeding type, nor could we perform multivariable regression analyses to test for possible confounding factors. Despite the fact that we performed several tests we chose not to correct for multiple testing, because we considered this observation to be exploratory and hypothesis generating. Another limitation concerns validity issues using NIRS to assess intestinal oxygenation. Movement of the gut, abdominal gasses, and stools could influence the signal because of absorption changes of the near-infrared light which is path-length dependent [6, 14, 31, 32, 35]. Additionally, standard limits of intestinal oxygen saturation are not yet established on account of the wide intervariability and intravariability of intestinal rSO₂ values [14, 16]. Finally, we clustered our data to determine whether the effect of enteral feeding on the intestinal rSO₂ depends on PMA. Therefore the contribution of measurements per infant was unequally distributed and we might have underestimated or overestimated our results. Nevertheless, to our knowledge, this is the first longitudinal study demonstrating that enteral feeding only affects intestinal oxygen saturation after weeks, or when infants have reached 32 weeks PMA, and larger volumes of feeds.

Our results suggest that postprandial intestinal hyperaemia does only occur at group level from the fifth week after birth or in infants with relatively older corrected gestational ages receiving a greater amount of enteral feeding. In addition, we showed that postprandial intestinal hyperaemia is not associated with compromised cerebral perfusion. Our study provides more insight into the intestinal physiologic response to enteral feeding in preterm infants. A better understanding of this intestinal physiologic postprandial response might support clinicians in identifying infants at risk for the development of GI complications. This exploratory study, however, raises questions about when and why intestinal saturation does or does not increase after enteral bolus feeding in the early postnatal weeks of a preterm infant, and whether a decreasing intestinal perfusion after feeding may be associated with GI complications later on. Further study is required to address these issues. Moreover, larger studies addressing possible confounders on the intestinal haemodynamic response to enteral feeds, such as PDA and other perinatal morbidities, are needed.