Intra-uterine growth restriction (IUGR) caused by placental insufficiency is characterized by blood flow redistribution to the vital organs (brain, myocardium, and adrenal glands), while other organs, including the gastrointestinal tract, are deprived from sufficient blood flow. As a consequence of gut ischemia/hypoxia, IUGR infants are thought to have impaired gut function after birth, which may result in intestinal disturbances, ranging from temporary intolerance to the enteral feeding to full-blown NEC.
In literature, however, there is no consensus regarding the impact of enteral feeding on intestinal blood flow and hence regarding the best regimen and the best rate of delivering the enteral nutrition.
Doppler ultrasonography is the method currently used for the clinical assessment of velocity of superior mesenteric artery blood flow . Blood flows parameters in the superior mesenteric artery (SMA) change with vasoconstriction or vasodilatation of the intestinal vascular bed. Prenatal utero-placental insufficiency with chronic fetal hypoxia can lead to foetal growth retardation with a redistribution of blood flow favouring the cerebral circulation and reducing mesenteric perfusion . This underlines the importance of chronic or acute hypoxia as the most intensively studied condition associated with disturbances of intestinal motility.
The possible association between the increase in blood flow velocity and change in tissue oxygenation is expected. Greater understanding of the rate of oxygen delivery and uptake in sick preterm infants undergoing intensive care is an important aim of neonatal medicine.
The assessment of adequate perfusion in very low birth weight infants is commonly based on clinical parameters, as well as invasive measures requiring central venous and/or arterial catheter access with well established associated risks. Additionally, most of these data are acquired intermittently, and thus may only represent a delayed picture of oxygen delivery and consumption.
Near-infrared spectroscopy (NIRS) is a continuous, non-invasive, real-time and portable techinique, which can be used to measure oxygenation in living tissue .
In 1985, Brazy and Lewis  reported the first pediatric application of NIRS monitoring of cerebral oxygenation in sick preterm infants. Since then the list of publications on NIRS for hemodynamic and oxygenation assessment in children and adults has rapidly expanded [5, 6].
The technological background of NIRS technology has been reviewed in detail . The main principle upon which NIRS device relies is the fact that most biological tissues, other than haemoglobin and cytochrome oxidase, are relatively transparent to infrared light in the range closest to the visual spectrum (700–1000 nanometers), and that the absorbance spectrum of the haemoglobin depends on its oxygenation status (deoxygenated haemoglobin absorbs more red light and less infrared light than oxygenated haemoglobin). All devices emit lights at wavelengths within the above mentioned spectrum and analyze photons returning to the transducer. Because the change in the intensity of the reflected light is dependent upon the oxyhemoglobin to deoxyhemoglobin ratio, oxyhemoglobin saturation can be derived . There are many different NIRS devices available. We use the INVOS cerebral oximeter (Somanetics Corporation, Troy, Michigan USA) that is FDA approved for adult and pediatric use including infants .
NIRS has been used to monitor oxygenation of the brain in neonates by measuring the ratio of oxygenated to deoxygenated hemoglobin (termed “tissue oxygenation index”, TOI) . NIRS has been reported to be useful in detecting changes in splanchnic oxygen delivery and predicting splanchnic ischemia in neonates by measuring the ratio of splanchnic to cerebral TOI, the cerebrosplanchnic oxygenation ratio (CSOR). Splanchnic oxygenation is compared with brain oxygenation as a reference, because under most of physiological conditions cerebral blood flow autoregulation minimizes changes in brain oxygenation during events affecting splanchnic perfusion .
A significant concern with the application of NIRS to the abdomen is the possibility of movement of the gut within the abdomen and also movement produced by peristalsis of the gut wall. These two movements can alter the scattering path of the near infrared light, resulting in absorption changes, which would swamp the signal of interest [12, 13]. However TOI now offers a method of comparing the haemoglobin redox status within the splanchnic circulation, which is not path-length-dependent because it provides a simultaneous ratio of oxyhaemoglobin to deoxyhaemoglobin. Finally, by measuring the TOI of the brain, which is preferentially autoregulated with the splanchnic region under most physiological conditions, the resultant CSOR ratio gives absolute values, which allow comparison between individual patients. CSOR had a 90% (56-100%) sensitivity to detect splanchnic ischaemia in neonates .
Regional tissue oxygenation of some other vascular beds and its clinical relevance is under review in extremely low birth weight infants .
In an effort to decrease the risk for development of NEC in preterm infants, enteral nutrition is often delayed when the neonate shows signs of feeding intolerance. However, enteral fasting can predispose a neonate to impaired intestinal growth, mucosal atrophy, intestinal barrier dysfunction, decreased digestive and absorptive capacity, increased colonization with pathogenic bacteria, and systemic inflammation. In addition, enteral fasting can prolong the time to establish full enteral feeding and the length of hospital stay . Consequently, minimal enteral feeding (MEF) in combination with parenteral nutrition (PN) is often employed to alleviate the side effects of enteral fasting in premature infants. MEF is thought to promote intestinal motility, to maintain the intestinal barrier, to stimulate the development of “good” microflora, and to reduce infections.
Tube feeding is necessary for most premature infants less than 1500 grams because of their inability to coordinate sucking, swallowing, and breathing and the risk of aspiration. The conventional tube feeding method is intermittent bolus gavage feeding, where a prescribed volume of milk is given over a short period of time, usually over 10 to 20 minutes by gravity. Some clinicians prefer the continuous nasogastric route to feed premature infants less than 1500 grams birth weight, although, in practice, intermittent bolus gavage feeding is the method more commonly used [17, 18]. In our Unit VLBW infants are fed by boluses, although they are often empirically switched to the continuous infusion method without an established rationale. Theoretical risks and benefits of both continuous nasogastric milk feeding and intermittent bolus milk feeding have been proposed. Continuous nasogastric feedings may improve energy efficiency (by increasing energy absorbed and decreasing energy expenditure), reduce feeding intolerance, improve nutrient absorption, and improve growth. However, continuous infusion of milk into the gastrointestinal tract could alter the cyclical pattern of release of gastrointestinal tract hormones, which might affect metabolic homeostasis, and growth. Milk feedings given by bolus gavage method are thought to be more physiologic because they promote the cyclical surges of gastrointestinal tract hormones normally seen in healthy term infants. On the other hand, functional limitations of the premature infant’s gastrointestinal system such as delayed gastric emptying or intestinal transit could hinder the premature infant’s ability to handle bolus milk feeds, resulting in feeding intolerance.
Additionally, this feeding regimen that alternates between periods of feeding and fasting may challenge the premature infant’s ability to maintain metabolic homeostasis and, therefore, decrease growth. There is still a debate about which is the best feeding regimen in order to prevent episodes of feeding intolerance and to promote a better growth.
Aims of the study
Primary aim of this study:
To evaluate the changes in the intestinal perfusion and oximetry determined by feeding in VLBW infants fed by 3 hours nasogastric nutrition (CN) versus infants fed by bolus nutrition (BN).
Secondary aims of the study:
To compare if changes in the intestinal perfusion and oximetry induced by feeding are different between IUGR and NON-IUGR infants.
To compare growth and nutritional status of the 2 groups by randomized arm.
To test if changes in intestinal oximetry and perfusion can be reliable predictors of feeding intolerance (days necessary to achieve full enteral feeding).
The endpoint for the primary aim will be the cross-over difference of CSOR values, measured with NIRS before and at the end of the randomized feeds.
Aims 1 to 4 will be pursued analysing the following endpoints:
· The cross-over difference of CSOR values and of rSO2s values (i.e. the splanchnic saturation slope) in IUGR and non-IUGR infants.
Growth and nutritional status will be measured by weight, length and head circumference. Main comparison will be between measures at randomization and at achievement of full enteral feeding. The growth at 28 days of life and at 36 weeks of gestational age will also be compared with the appropriate standard growth curves.
The difference in the CSOR values pre- and post- feeding will be compared with the baseline CSOR value and the baseline Doppler flow velocimetry (both measured within the first 72 hours of life).
Comparison of the time needed to reach full enteral feeding (i.e. days from randomization till enteral intake of 160 ml/kg/day of formula or fortified human milk) by randomized arm;