Dani, Carlo; Pratesi, Simone; Barp, Jacopo; Bertini, Giovanna; Gozzini, Elena; Mele, Laura; Parrini, Letizia
Nutritional practices strongly influence the outcome of extremely preterm infants and many studies have investigated their complete feeding requirements. Although randomized controlled trials are still needed to elucidate different aspects of intravenous and enteral nutrition strategies (1,2), it is evident that these infants require early intravenous feeding; however, the early initiation of enteral nutrition limits the risk of developing catheter-related bloodstream infections (1–3) and decreases the time needed to regain birth weight and reach full enteral feedings, without increasing the incidence of necrotizing enterocolitis (NEC) (1–3). Breast milk is the optimal food for preterm infants. Nearly all studies demonstrate that it confers a protective advantage against the development of NEC (4–8). This advantage appears specific to fresh milk from each infant's own mother, and not to donors’ milk, although this issue is still debated (8,9); however, human milk does not always meet the preterm infant's increased nutrient and protein demand (10). In fact, standard fortification of human milk has been shown to increase growth in preterm infants (11).
There have been different trials to determine the best mode of enteral feeding (12–18). A recent meta-analysis of these studies has shown that there were no differences in time to achieve full enteral feeds, somatic growth, and incidence of NEC between these 2 feeding methods (19).
On the contrary, Fang et al showed that there is a significant correlation between an increase in superior mesenteric artery (SMA) blood flow velocity (BFV) and early tolerance of enteral feeding in preterm infants (20). Nonetheless, several authors have found that BFV in the SMA is lower in the small-for-gestational age (SGA) than in appropriate-for-gestational age (AGA) preterm infants (21–23), and we demonstrated that SGA preterm infants with prenatal hemodynamic disturbances do not show the physiological postprandial increase in BFV of SMA (24).
Use of near-infrared spectroscopy (NIRS) has permitted the noninvasive measurement of splanchnic regional oxygenation (rSO2S), which has been studied in the preterm infant in different clinical conditions, such as during acute abdominal pathologies (25) or after blood transfusions (26). Recently, Dave et al (27) showed that splanchnic oxygenation, measured as tissue oxygenation index, increases significantly after feeding in stable preterm infants who are tolerating full bolus orogastric feeds.
On this basis, we hypothesized that continuous and intermittent bolus milk feeding may affect the rSO2S differently, and that this effect may differ between AGA and SGA preterm infants. To assess this hypothesis, we prospectively studied 2 cohorts of AGA and SGA preterm infants in whom rSO2S was measured by NIRS during continuous and intermittent milk enteral feeding. In addition, Doppler ultrasonography was used to measure BFV in SMA.
A prospective center-based study was carried out at the neonatal intensive care unit of Careggi University Hospital of Florence. The study was approved by the local ethics committee. Infants of gestational age <32 weeks were enrolled in the study, after parental informed consent, if they were clinically stable and tolerating full bolus feeds for 1 week with a total daily amount between 140 and 160 mL/kg, without intravenous support. Eligibility for the study also included tolerance of orogastric tube feeding by gravity during a period of 5 to 10 minutes given every 3 hours, on the day of the study.
Exclusion criteria were the need of cardiovascular support, signs of abdominal distension, previous NEC, gastroschisis or congenital diaphragmatic hernia, and infection developing within 1 week before enrollment. These exclusion criteria were selected because catecholamine administration may reduce perfusion by pathological vasoconstriction and because of concerns over the integrity of splanchnic perfusion following pathological gastrointestinal disorders.
Enrolled patients were classified as AGA or SGA if their birth weight was >10th or <10th percentile for gestational age. Moreover, SGA neonates were enrolled only if they had prenatal hemodynamic disturbances (intrauterine growth restriction) (24). We defined prenatal hemodynamic disturbance as, together with growth velocity delay, abnormalities of umbilical artery, ductus venous, and middle cerebral artery Doppler studies (28).
Each infant was given a milk bolus for ∼10 minutes (intermittent feeding) followed after 3 hours (measured from the start of bolus feeding) by a 3-hour continuous feeding, which delivered the same milk volume as the bolus. The previous feeding regimen was restarted 1 hour after the end of continuous feeding. All of the patients received their mother's or donor's human milk, which was administered through an orogastric tube that was connected to a syringe infusion pump for continuous feeding.
All of the measurements were taken with each infant in the supine position. During data recording, infants were mostly quiet or sleeping and, to reduce NIRS artefacts, the handling of patients during the study period was minimized. Oxygen arterial saturation (SaO2) and heart rate (Passport 2, Datascope Corp, Mahwah, NJ) were continuously recorded.
The following variables were recorded for each patient: gestational age, birth weight, sex, type of delivery, age and weight at study, milk feeding volume, duration of parenteral nutrition, number of feeding stops before the achievement of full enteral feeding and occurrence of respiratory distress syndrome, need of surfactant, oxygen therapy duration, patent ductus arteriosus, all-grade intraventricular hemorrhage, NEC, bronchopulmonary dysplasia, and length of hospital stay. Bronchopulmonary dysplasia was defined as oxygen requirement at 36 weeks of postconceptional age (29).
Enrolled patients were studied continuously by NIRS (INVOS 5100, Somanetics Corporation, Troy, MI) for measurement of rSO2S from 30 minutes before the beginning of bolus feeding to 30 minutes after the end of continuous feeding with a sampling interval of 6 seconds. A self-adhesive transducer, which contains a light-emitting diode and 2 distant sensors, was fixed to the abdomen just below the umbilicus for rSO2S recording. The rSO2 measurements obtained with the NIRS technique reflect a combination of intravascular oxygenated/deoxygenated venous, arterial, and capillary hemoglobin in a ratio of approximately 75:20:5 (30).
Based on the measurements of rSO2S and SaO2, we calculated the splanchnic fractional oxygen extraction ratio (FOES [S = splanchnic]) (25), which is the difference between arterial SaO2 measured by pulse oximetry and the organ tissue oxygen saturation (rSO2) measured by NIRS (FOES = [SaO2−rSO2]/SaO2). This parameter reflects the balance between oxygen delivery and oxygen consumption. Therefore, an increase in FOES suggests an increase in the oxygen extraction by tissues, because of higher oxygen consumption in relation to oxygen delivery, whereas its decrease suggests less oxygen use in comparison with the supply (31).
All of the NIRS data were recorded 30 minutes before (T0) and 30 minutes after the beginning of bolus feeding (T1), 30 minutes before (T2), at the end (T3), and 30 minutes after the continuous feeding period (T4). We chose to report NIRS data at the end of the continuous feeding period and not after 30 minutes as for bolus feeding, because we estimated that the effects on rSO2S and FOES increase over time; however, rSO2 and FOES mean values were similar after 30 minutes and 3 hours of continuous feeding (unreported data).
Splanchnic Doppler Ultrasound Measurements
Splanchnic BFV was studied in the SMA using 2-dimensional Doppler ultrasounds with a spectral analyzer (Philips Sonos 7500 Ultrasound, Andover, CT). Five sequential cardiac cycles of optimal quality (maximal amplitude of the velocity curves) were recorded at each study time, maintaining the angle of insonation <15°. Peak systolic velocity (PSV), diastolic velocity, mean flow velocity (Vmean), and resistance index (RI) (32) were recorded along with NIRS data.
In planning our study, we calculated that a sample size of at least 12 infants was required to detect a statistically significant increase of 10% of rSO2S 30 minutes after the bolus feeding (T2) with 80% power at 0.05 level.
For each NIRS variable (rSO2S, FOES), we calculated the mean (±SD) from selected 5-minute periods, which were chosen at the end of T0, T1, T2, T3, and T4(26). On the contrary, sometimes this was not possible because of the occurrence of unwanted artifacts (generally infant movements); in this case the 5-minute period without artifacts closest to the end of T0, T1, T2, T3, and T4 was selected. Ultrasound data (PSV, diastolic velocity, Vmean, RI) were reported as means (±SDs).
Serial measurements of studied variables were compared by repeated-measures analysis of variance, whereas comparisons between the rSO2S and FOES of AGA and SGA infants were performed using the Student t test for parametric data because our data have a normal distribution. P < 0.05 was considered statistically significant.
Twelve AGA and 12 SGA infants were enrolled in the study. Clinical characteristics of the 2 groups were similar, with the exception of surfactant treatment (Table 1). The 2 groups were studied at the mean age of 45 ± 16 and 49 ± 17 days of life, respectively. One infant in the AGA group died of sepsis. Infants’ heart rate and SaO2 did not change during the study in either group (Table 2).
We observed that rSO2S increased at T1 in both AGA and SGA groups, whereas FOES did not vary during the study period. Moreover, we found that rSO2S and FOES at T1 and T3 were respectively higher and lower in AGA than in SGA infants (Tables 3 and 4).
The mean values of PSV and Vmean in the SMA significantly increased at T1 compared with baseline and then decreased in both groups. RI did not vary during the study period (Tables 5 and 6).
This is the first study that investigates the effects of continuous and intermittent bolus milk feeding on rSO2S and FOES in preterm infants and compares these effects in AGA and SGA infants.
We observed that rSO2S increased 30 minutes after bolus feeding in both AGA and SGA preterm infants, whereas the FOES did not vary. Similarly, we found that BFV in the SMA significantly increased in both the groups 30 minutes after bolus feeding. Although changes in BFV do not always mean changes in tissue blood perfusion (ie, only when the cross-sectional area of the vessel remains constant is BFV the major determinant of tissue blood volume), BFV is related to tissue blood flow (33) in neonates in stable clinical condition, as was our population. Thus, our results suggest that bolus feeding is followed by an increase in splanchnic perfusion, which improves splanchnic oxygenation; however, the stability of FOES indicates that the tissue oxygenation in our patients was adequate and did not require an increase or decrease in oxygen blood extraction. Our data are in agreement with previous studies: Petros et al reported 1 infant with a postprandial increase in gastrointestinal blood volume and oxygen delivery to the gut (34), and Dave et al (27) found that splanchnic oxygenation increases significantly after feeding in stable preterm infants; however, the observed postprandial increase in splanchnic tissue oxygenation is expected given the postprandial increase in SMA BFV observed using Doppler studies (20,23,35–38).
Another important finding of our study is that SGA and AGA infants showed a similar increase in rSO2S and BFV in the SMA after bolus feeding. In fact, this demonstrates that SGA infants, who were previously found unable to develop the physiological postprandial increase of BFV in the SMA after the first feeding (24), can subsequently acquire this capacity (at 46 ± 16 days of life in our population) when they are tolerating full orogastric feeds.
Conversely, rSO2S, FOES, and BFV in the SMA did not vary during continuous feeding in either AGA or SGA infants. These findings suggest that this mode of enteral feedings does not increase the intestinal oxygen requirement and, therefore, is not associated with an increase in blood flow, tissue oxygenation, or oxygen blood extraction. We speculate that this may occur because of the lower gastrointestinal workload occurring during continuous enteral feeding in comparison with intermittent bolus feeding because of the delivery of a continuous small enteral volume instead of an intermittent higher volume (7.3 ± 1.2 mL · kg−1 · h−1 vs 22 ± 6 mL/kg every 3 hours). Unfortunately, these results cannot be compared with other data from the literature because this topic has never been studied before; however, they are in agreement with a previous finding that energy expenditure (and oxygen need) in preterm infants is significantly greater after intermittent than after continuous feeding (39). Therefore, it may be hypothesized that the absence of additional oxygen requirement associated with continuous enteral feeding may help limit the possibility of developing hypoxic-ischemic gut damage and NEC in high-risk preterm infants.
Our data demonstrate for the first time that rSO2S is higher and FOES is lower in AGA than in SGA infants when they tolerate full enteral feeding. This occurs during both bolus and continuous feeding and indicates that lower gut oxygenation is compensated for by higher oxygen blood extraction in SGA infants. This condition could be because of the lower postnatal gastrointestinal perfusion occurring in SGA infants with prenatal hemodynamic disturbance, which has been previously reported by several authors (21–23), and that in our patients lasted for several weeks. Although these findings in our SGA infants do not seem to have immediate clinical relevance because they were in good clinical condition and tolerated full enteral feeding well, it is possible that their low intestinal oxygenation limits the gut's ability to meet the additional metabolic demand that feeding imposes, increasing the risk of hypoxic-ischemic gastrointestinal damage and NEC (40).
In conclusion, our study demonstrates that bolus milk feeding induces an increase in splanchnic oxygenation without increasing oxygen blood extraction in both healthy AGA and SGA infants, whereas continuous feeding does not affect gastrointestinal oxygenation. Our data show that splanchnic oxygenation is higher (and oxygen blood extraction is lower) in AGA than in SGA infants both during bolus and continuous feeding. Although this difference is not clinically relevant in healthy preterm infants, it may become important in those in critical condition, especially SGA infants, in whom continuous feeding could help limit the risk of hypoxic-ischemic gut damage.
1. Hay WW Jr. Strategies for feeding the preterm infant. Neonatology 2008; 94:245–254.
2. Ehrenkranz RA, Das A, Wrage LA, et al. Early nutrition mediates the influence of severity of illness on extremely LBW infants. Pediatr Res 2011; 69:522–529.
3. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotizing enterocolitis in very low birth weight infants. Cochrane Database Syst Rev 2011; 16:CD001970.
4. Lucas A, Cole TJ. Breast milk and neonatal necrotizing enterocolitis. Lancet 1990; 336:1519–1523.
5. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants: beneficial outcomes of feeding fortified human milk versus preterm formula. Pediatrics 1999; 103:1150–1157.
6. Sisk PM, Lovelady CA, Dillard RG, et al. Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J Perinatol 2007; 27:428–433.
7. McGuire W, Anthony MY. Donor human milk versus formula for preventing necrotizing enterocolitis in preterm infants: systematic review. Arch Dis Child Fetal Neonatal Ed 2003; 88:11–14.
8. Boyd CA, Quigley MA, Brocklehurst P. Donor breast milk versus infant formula for preterm infants: systematic review and metaanalysis. Arch Dis Child Fetal Neonatal Ed 2007; 92:169–175.
9. Schanler RJ, Lau C, Hurst NM, et al. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics 2005; 116:400–406.
10. Kuschel CA, Harding JE. Protein supplementation of human milk for promotinggrowth in preterm infants. Cochrane Database Syst Rev 2000; 3:CD000433.
11. Kuschel C, Harding J. Multicomponent fortified human milk for promoting growthin preterm infants. Cochrane Database Syst Rev 2004; 1:CDC000343.
12. Toce SS, Keenan WJ, Homan SM. Enteral feeding in very low- birth-weight infants. A comparison of two nasogastric methods. Am J Dis Child 1987; 141:439–444.
13. Silvestre MA, Morbach CA, Brans YW, et al. A prospective randomized trial comparing continuous versus intermittent feeding method in very low birth weight neonates. J Pediatr 1996; 128:748–752.
14. Akintorin SM, Kamat M, Pildes RS, et al. A prospective randomized trial of feeding methods in very low birth weight infants. Pediatrics 1997; 100:E4.
15. Dollberg S, Kuint J, Mazkereth R, et al. Feeding tolerance in preterm infants: randomized trial of bolus and continuous feeding. J Am Coll Nutr 2000; 19:797–800.
16. Dsilna A, Christensson K, Alfredsson L, et al. Continuous feeding promotes gastrointestinal tolerance and growth in very low birth weight infants. J Pediatr 2005; 147:43–49.
17. Macdonald PD, Skeoch CH, Carse H, et al. Randomised trial of continuous nasogastric, bolus nasogastric, and transpyloric feeding in infants of birth weight under 1400 g. Arch Dis Child 1992; 67:429–431.
18. Schanler RJ, Shulman RJ, Lau C, et al. Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics 1999; 103:434–439.
19. Premji SS, Chessell L. Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams. Cochrane Database Syst Rev 2011; 11:CD001819.
20. Fang S, Kempley ST, Gamsu HR. Prediction of early tolerance to enteral feeding in preterm infants by measurement of superior mesenteric artery blood flow velocity. Arch Dis Child Fetal Neonatal Ed 2001; 85:F42–F45.
21. Maruyama K, Koizumi T. Superior mesenteric artery blood flow velocity in small for gestational age infants of very low birth weight during the early neonatal period. J Perinat Med 2001; 29:64–70.
22. Martinussen M, Brubakk AM, Vik T, et al. Relationship between intrauterine growth retardation and early postnatal superior mesenteric artery blood flow velocity. Biol Neonate 1997; 71:22–30.
23. Kempley ST, Gamsu HR, Vyas S, et al. Effects of intrauterine growth retardation on postnatal visceral and cerebral blood flow velocity. Arch Dis Child 1991; 66:1115–1118.
24. Pezzati M, Dani C, Tronchin M, et al. Prediction of early tolerance to enteral feeding by measurement of superior mesenteric artery blood flow velocity: appropriate- versus small-for-gestational-age preterm infants. Acta Paediatr 2004; 93:797–802.
25. Fortune PM, Wagstaff M, Petros AJ. Cerebro splanchnic oxygenation ratio (CSOR) using near infrared spectroscopy may be able to predict splanchnic ischaemia in neonates. Intensive Care Med 2001; 27:1410–1417.
26. Dani C, Pratesi S, Fontanelli G, et al. Blood transfusions increase cerebral, splanchnic, and renal oxygenation in anemic preterm infants. Transfusion 2010; 50:1220–1226.
27. Dave V, Brion LP, Campbell DE, et al. Splanchnic tissue oxygenation, but not brain tissue oxygenation, increases after feeds in stable preterm neonates tolerating full bolus orogastric feeding. J Perinatol 2009; 29:213–218.
28. Baschat AA. Fetal growth restriction—from observation to intervention. J Perinat Med 2010; 383:239–246.
29. Ehrenkranz RA, Walsh MC, Vohr BR, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116:1353–1360.
30. Wardle SP, Yoxall CW, Weindling AM. Determinants of cerebral fractional oxygen extraction using near infrared spectroscopy in preterm neonates. J Cereb Blood Flow Metab 2000; 20:272–279.
31. Naulaers G, Morren G, Van Huffel S, et al. Cerebral tissue oxygenation index in very premature infants. Arch Dis Child Fetal Neonatal Ed 2002; 87:F189–F192.
32. Pourcelot L. Donald I, Levi S. Diagnostic ultrasound for cerebral vascular disease. Present and Future of Diagnostic Ultrasound. Rotterdam:Kooyker Scientific Publications; 1976. 141–147.
33. Haaland K, Karlsson B, Skovlund E, et al. Simultaneous measurements of cerebral circulation with electromagnetic flowmetry and Doppler ultrasound velocity in the newborn pig. Pediatr Res 1994; 36:601–606.
34. Petros AJ, Heys R, Tasker RC, et al. Near infrared spectroscopy can detect changes in splanchnic oxygen delivery in neonates during apnoeic episodes. Eur J Pediatr 1999; 158:173–174.
35. Leidig E. Pulsed Doppler ultrasound blood flow measurements in the superior mesenteric artery of the newborn. Pediatr Radiol 1989; 19:169–173.
36. Ozkan H, Oren H, Erdag N, et al. Breast milk versus infant formulas: effects on intestinal blood flow in neonates. Indian J Pediatr 1994; 61:703–709.
37. Hsu CH, Lee HC, Huang FY. Duplex ultrasonographic assessment of gut blood flow velocity: effect of meal composition in normal full-term newborns after first feed. J Ultrasound Med 1994; 13:15–18.
38. Coombs RC, Morgan ME, Durbin GM, et al. Doppler assessment of human neonatal gut blood flow velocities: postnatal adaptation and response to feeds. J Pediatr Gastroenterol Nutr 1992; 15:6–12.
39. Grant J, Denne SC. Effect of intermittent versus continuous enteral feeding on energy expenditure in premature infants. J Pediatr 1991; 118:928–932.
40. Bora R, Mukhopadhyay K, Saxena AK, et al. Prediction of feed intolerance and necrotizing enterocolitis in neonates with absent end diastolic flow in umbilical artery and the correlation of feed intolerance with postnatal superior mesenteric artery flow. J Matern Fetal Neonatal Med 2009; 22:1092–1096.