- Email: [email protected]
Nutritional approach to preterm infants on noninvasive ventilation: An update
Accepted Manuscript Nutritional approach to preterm infants on non invasive ventilation: an update Valentina Bozzetti, MD PhD, Chiara De Angelis, MD, Paolo E. Tagliabue, MD. PII:
S0899-9007(16)30284-2
DOI:
10.1016/j.nut.2016.12.010
Reference:
NUT 9890
To appear in:
Nutrition
Received Date: 14 October 2016 Revised Date:
29 November 2016
Accepted Date: 17 December 2016
Please cite this article as: Bozzetti V, De Angelis C, Tagliabue PE, Nutritional approach to preterm infants on non invasive ventilation: an update, Nutrition (2017), doi: 10.1016/j.nut.2016.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Nutritional approach to preterm infants on non invasive ventilation: an update. Valentina Bozzetti MD PhD, Chiara De Angelis MD, Paolo E. Tagliabue MD.
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Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy;
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Corresponding Author: Valentina Bozzetti MD Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, via Pergolesi, 20900 Monza, Italy 0039 039 2339174 [email protected] Running title: Enteral nutrition for non-invasive ventilated infants.
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Chiara De Angelis MD email: [email protected] Paolo E Tagliabue MD email: [email protected]
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All the Authors revised the literature, wrote the paper and revised the paper approving the
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last version to be submitted
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Abstract
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Nutrition and pulmonary function in very low birth weight [VLBW] infants are strictly
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related. Preterm infants on non invasive ventilation [NIV] may have respiratory
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instability that can interfere with feeding tolerance. Moreover, feeding may impair
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pulmonary function. Those infants have nutritional requirements different than non
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ventilated infants. The main challenge of the nutritional support in such patients is to
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guarantee adequate caloric intake while avoiding episodes of feeding intolerance. This
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paper reviews the issues and the strategies of enteral feeding of preterm infants on NIV.
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Non invasive ventilation, enteral nutrition, preterm infants, growth, nutritional
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requirements.
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Background
2 Nutrition and pulmonary function in very low birth weight (VLBW) infants are strictly
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related. While maintaining an optimal pulmonary function has priority in the VLBW
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infants to secure vital functions, an adequate nutritional support plays a major role
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because a state of malnutrition not only compromises growth in general, but it has major
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adverse effects on the respiratory system. For instance, inadequate early nutrition may
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contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) by hampering the
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process of lung repair in the first month of life [1]. VLBW infants, growing along the
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lower quartiles during their neonatal stay, are at higher risk for neurodevelopmental
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damage as well as chronic pulmonary complications [2]. On the other hand, infants with
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respiratory problems often experience poor growth and delayed development [3].
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As a matter of fact, infants with respiratory impairment on non-invasive ventilation
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require an adequate nutritional assessment. We therefore performed a collective and
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narrative review to analyze the issues regarding feeding preterm infants with respiratory
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impairment.
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Methods
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The following electronic databases were searched until January 2016 for published
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studies that fulfilled our criteria: Cochrane Central Register of Controlled Trials and
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PubMed (including MEDLINE). To identify potential systematic reviews/meta-analyses,
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we browsed The Cochrane Database of Systematic Reviews.
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An initial screening of the title, abstract, and keywords of every record identified was
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performed. The next step was to retrieve the full text of potentially relevant studies. The
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following search terms were used: (enteral nutrition OR enteral feeding) AND (non-
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invasive ventilation OR continuous positive pressure airway pressure). Only studies in
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english and related to infant from birth to 23 months of age were considered.
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The impact of Non-Invasive Ventilation
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Although life-saving, invasive mechanical ventilation of VLBW infants represents a
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major risk factor for the development of BPD, Ventilator-Induced Lung Injury (VILI)
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and infection [4]. VILI is reported to be associated with alveolar structural damage,
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pulmonary oedema, inflammation, and fibrosis. Mechanisms of lung injury include high
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airway pressure (barotraumas), large gas volumes (volutrauma), alveolar collapse and re-
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expansion (atelectrauma), and increased inflammation (biotrauma). In VLBW infants,
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BPD remains a leading cause of early death and morbility. Improvements in survival
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rates among such infants have led to rates of BPD of up to 60% at the lowest gestational
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ages [5].
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These concerns have prompted neonatologists to use non-invasive modes of ventilation,
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and this approach has been increasingly gaining acceptance in most NICUs. Nasal
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continuous positive airway pressure (CPAP) is an alternative to intubation and
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intermittent positive-pressure ventilation (IPPV). A meta-analysis of trials of early nasal
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CPAP versus intubation and ventilation showed that nasal CPAP reduces the risk of
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bronchopulmonary dysplasia [6]. These findings led to a more extensive utilization of
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techniques of non-invasive ventilation in the NICUs.
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Non-invasive forms of ventilation in neonates can be provided either as a single level
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support such as CPAP and High Flow Nasal Cannula (HFNC) or bilevel support such as
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Nasal Intermittent Positive Pressure Ventilation (NIPPV). Nasal intermittent positive
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pressure ventilation is a method of augmenting NCPAP by delivering ventilator breaths
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via nasal prongs. NIPPV may be synchronised with the infant's inspiration or delivered
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independently of the infant's breathing efforts, and it is usually delivered at pressures
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similar to those used during conventional ventilation. Different modes of ventilation may
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be applied non-invasively, leading to different NIPPV terminologies such as N-SIMV
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[7], N-IMV [8] and NI-PSV [9]. Various interfaces have been used to deliver NIV such
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as by face masks, nasopharyngeal and nasal interfaces. Short binasal prongs are the most
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commonly used interface for NIPPV and BiPAP [10,11].
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There is no agreement on the best technique of non-invasive ventilation. In a recent trial,
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comparing the effect of different modalities of non-invasive ventilation on the survival
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rate at 36 weeks of postmenstrual age of extremely-low-birth-weight infants without
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BPD, there was no significant difference between non-invasive respiratory support with
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nasal IPPV as compared with nasal CPAP [12].
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Feeding Issues
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It has been commonly reported that infants on non-invasive ventilation suffered of
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marked gaseous bowel distension; initially this condition was termed as the “CPAP belly
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syndrome”. This picture was described in infants that did not present abdominal
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distension at birth, but developed it after a 4-7 days course of nasal CPAP. These infants
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presented strikingly distended abdomens and visibly dilated loops. Findings on
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radiographs invariably include uniform dilatation of small-bowel and large-bowel loops
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without evidence of thickening of the bowel wall, pneumatosis or free air [13].
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Jaile et al. [13] compared 25 premature infants on nasal CPAP with 29 premature infants
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who were not on CPAP. Gaseous bowel distension due to CPAP developed in 83% of
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infants below 1000 g versus 14% of those weighing ≥1000 g. Of the 29 infants not
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receiving nasal CPAP during the study period,
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gaseous
bowel
distension,
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indisintinguishable from CPAP belly syndrome, developed in only 3 (10%). No cases of
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NEC were reported in the study; however, the sample size was too small to draw
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conclusions about NEC.
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Correlates among ventilation, mesenteric flow and gastric emptying
Several authors have reported a correlation between CPAP ventilation and mesenteric
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blood flow. Havranek et al. [14] reported that CPAP administration was associated with
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an attenuation of the postnatal increase in superior mesenteric artery blood flow velocity
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(SMA BFV) in preterm infants. [15]. Increase in SMA BFV is strictly related to feedings
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in stable infants [16] and attenuated increases in postnatal SMA BFV were associated
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with intestinal dysmotility [17] and with feeding intolerance. In a further study the
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increase in SMA BFV after feeding was measured, showing a higher increase of BFV in
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SMA from 0 to 30 min after feeding, that was greater when infants were on CPAP versus
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off CPAP. The higher increase in SMA BFV from 0 to 30 min after feeding while on
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CPAP may relate to effects of this way of ventilation on gastric emptying time. The gut
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blood flow depends on gastric emptying and feeding progression through the
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gastrointestinal tract [18-21]. The continuous positive airway pressure exerted by the
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cPAP may exert a pressure on the diaphragm thus increasing the velocity of gastric
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emptying [22].
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The clinical implications of earlier maximum postprandial SMA BFV or shorter gastric
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emptying times in this population are not known. However, a delayed gastric emptying of
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preterm infants is associated with feeding intolerance. As the way of ventilation may
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interfere with the gastrointestinal function, feeding too may impact on pulmonary
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dynamics.
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A number of Authors have speculated on the effects of the abdominal body wall and of
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the abdominal contents on the mechanics of respiration. In a study by Yu and Rolfe [23],
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pulmonary function was measured at rest and after feeding [administered as tube feeding
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by the gravity method] in infants suffering from respiratory distress syndrome (RDS) and
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in healthy infants. They used a pneumotachograph with an adaptator during spontaneous
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breathing. In infants with RDS, the respiratory rate was raised, tidal volume decreased,
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and minute ventilation increased. Compliance was reduced to one-quarter the normal
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value. Resistance was essentially unchanged, but the decrease in compliance contributed
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to a greatly increased the work of breathing. The hypothesis is that the reduction in
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functional residual capacity (FRC) after feeding might be associated with a raised
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transpulmonary pressure which causes airways closure, either de novo or to a greater
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extent than before feeding.
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There are still controversies regarding the best tolerated feeding method since the impact
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of feeding method, intermittent or continuous, upon respiratory mechanics in VLBW
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infants remains unclear. Studies in the literature are small, rather old and inconsistent.
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Blondheim et al [24] measured the dynamic respiratory function of two groups of infants
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randomly assigned to be fed intermittently or continuously. These Authors found that
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bolus gavage of 15±20 mL of milk per kg decreased tidal volume, minute ventilation, and
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dynamic compliance and increased resistance within 10 min after feeds. In a more recent
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study, Brar et al. [25] found no adverse effect of intermittent versus continuous feeding
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on respiratory system compliance and resistance, tidal volume, or FRC after feeding in
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stable full enteral fed VLBW infants thus stating that the two feeding methods were
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equivalent. Results from the two mentioned studies are conflicting (one assessing that
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bolus feeding impaired respiratory patterns, the other stating that the impact of the two
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different feeding modalities on respiratory function was the same) as the accuracy in
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pleural pressure estimation used for dynamic measurement of respiratory mechanics was
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different. In the study by Blondheim, the infants examined were VLBW preterm infants
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with RDS; Brar et al. instead evaluated at term infants. It is possible that the different
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pulmonary response to feeding might be influenced by prematurity.
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Continuous feeding infusion may result in significant higher losses of energy, mainly in
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the form of fat and protein from human milk compared with intermittent infusion. It has
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been shown that human breast milk leaves a fatty residue in the burette and in the tube at
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the end of the infusion. There is some evidence that these losses are inversely related to
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flow rates. Fat and protein loss during tube feeding could adversely affect growth
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supplying lower energy amounts as well as deprive infants of very low chain
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polyunsaturated fatty acids needed for brain and nervous system development. [26,27]
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There may be some advantages to feed in the prone position even though these benefits
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may be offset by the tendency of these infants to exhibit a higher body temperature while
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in this position [28].
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A recent Cochrane review [29] comparing the rates of gastric distension, gastrointestinal
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perforation, necrotising enterocolitis with NIPPV versus nCPAP, found no significant
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difference for any variables between the groups. So the different modalities of non-
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invasive ventilation could be used indifferently according to the gastrointestinal issues.
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Planning nutrition
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Enteral feedings are usually started in the first two to five days after birth to prime the
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gastrointestinal (GI) tract in preterm infants.
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In a systematic review, the actual volume of trophic feeds ranged from 10 to 25
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mL/kg/day and onset from day one of life onwards [30]. Early introduction of trophic
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feeds compared to fasting had a non-significant trend towards reaching full feeds earlier
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and no difference in NEC frequency as compared to fasting. In a review focusing on
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timing of introduction of nutritional enteral feeding to prevent NEC [31], early
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introduction of progressive enteral feeding (1 to 2 days of age) did not increase the risk of
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NEC, mortality or feed intolerance. Both these reviews addressed feeding questions on
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VLBW or preterm infants without stratifying the analysis among ventilated or not
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ventilated infants. So it is reasonable, when planning nutrition of non-invasive ventilated
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infants, to follow the same schedule of preterm infants without RDS about timing of
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introduction and of progression of enteral feeding.
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Providing adequate nutrition is crucial in reducing the risk and severity of RDS [32].
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High fluid was thought to increase the risk of developing BPD through the persistence of
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PDA and the occurrence of a higher fluid content in the pulmonary interstitial tissue.
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These conditions could contribute to decrease lung compliance and increase the need for
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respiratory support (i.e: oxygen and mechanical ventilation) and therefore could worsen
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the course of RDS and increase the risk of lung injury and BPD. According to a Cochrane
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review, modest restriction of fluid intake increases an early weight loss but has positive
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effect in terms of reducing PDA and NEC [33]. The risk of BPD is not significantly
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affected by water intake in any of the trials analyzed. The fluid intake therefore should be
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individualized according the fluid balance, weight changes and serum electrolyte levels
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[34].
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Infants on ventilation may present growth delay. The etiology of this delayed growth
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performance is multifactorial including limited nutrient intake because of restricted fluid
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intake, feeding intolerance and/or prolonged parenteral nutrition, extreme prematurity,
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and the interference with growth processes by exogenous steroids, which are often
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prescribed to enhance pulmonary compliance. Moreover, it is commonly assumed that
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infants with RDS have an increase in energy expenditure (EE) due to increase of O2
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consumption, CO2 production, rest energy expenditure and work of breathing. [35,36]
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Limitations in study designs and measurement techniques have complicated the
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interpretation of EE determinations in infants with pulmonary insufficiency. The usual
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measurement of EE requires complicated equipment, which may affect the subject’s
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environmental and behavioral pattern, making it impractical for a routine clinical
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investigation. The double labeled water (DLW) is sensitive to analytic error when used to
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measure EE in preterm infants, because preterm infants have a high growth rate, high
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body water content, and high water turnover relative to CO2 production [37].
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ESPGHAN [38] Committee on Nutrition published the nutritional requirements for
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preterm infants and reported as
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preterm infants 110-135 kcal/kg/d. Total energy needs in infants with respiratory distress
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may increase up to 150 kcal/kg per day because of increased resting energy expenditure,
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respiratory workload, activity, and insensible water losses [39]. Oxygen consumption,
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energy expenditure and work load are higher for infants with respiratory problems who
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are breathing spontaneously than for those on assisted ventilation therefore their total
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energy expenditure is strictly associated with their respiratory status.
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Based on the protein needs and nitrogen utilization, the protein intake should be at least
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3.0 g/kg/day. Protein supply needs to compensate for the accumulated protein deficit
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observed in almost all small preterm infants, and can be increased to a maximum of 4.5
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g/kg/day, depending on the magnitude of the accumulated protein deficit.
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The ESPGHAN Committee on Nutrition [40] and the expert committee convened by the
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US Life Science Research Office [39] recommended fat intake upper limits of 6.0 g/100
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kcal [40] and of 5.7 g/100 kcal [41].
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Ventilated infants with restricted fluid and feed intakes due to feeding intolerance may
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need high fat intakes to meet energy needs, for most preterm infants a reasonable range of
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fat intake is 4.8 to 6.6 g/Kg/d or 4.4 to 6.0 g/100 kcal. The medium-chain triglyceride
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energy intake recommendation of healthy growing
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content in preterm formulae, if added, should be in the range of up to 40% of the total fat
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content [40].
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Since the coefficient of fat absorption decreases with increasing chain length and
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increases with increasing number of double bonds of the fatty acid, high concentrations
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of MCTs have been used in some preterm formulas to increase the coefficient of fat
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absorption of preterm infants [42].
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Moreover, due to the high caloric density of lipids emulsion, these are a good energy
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source in clinical condition requiring fluid restriction.
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Since hyperlipidemia can cause pulmonary dysfunction, including hemorrhage, liver
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damage and coagulopathy, guidelines about lipids supplementation are prudent regarding
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the use of lipids in special disease conditions; it is recommended to adjust the delivery of
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intravenous lipids to plasma triglyceride concentrations [42].
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Conclusion
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Non-invasive ventilated infants may experience growth delay for multiple reasons. The
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main challenge of the nutritional support in such patients is to guarantee adequate caloric
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intake while avoiding episodes of feeding intolerance.
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The knowledge about the nutritional requirements, energy expenditure and feeding
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tolerance in infants with pulmonary dysfunction is scanty and rather old; hence it is
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difficult to make universal recommendations regarding the adequate kind of nutrition and
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feeding method for premature infants with pulmonary impairment from studies
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characterized by small sample sizes and with methodological limitations.
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Moreover, the population evaluated in the studies is quite heterogeneous. The associated
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morbidities and the severity of the respiratory impairment may be very different among
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infants on non-invasive ventilation, therefore the nutritional requirements, the risk of
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feeding intolerance and consequently the impact on growth can be deeply different
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among patients.
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Future research should encompass different aspects: firstly it should adopt modern and
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reliable instrumentations for assessing the energy expenditure and specific nutrient
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requirements of infants with pulmonary impairment. So it would be possible to correlate
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the energy expenditure of the infants and subsequently personalize the energy intake.
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Secondly, it would be quite important to identify early indicators and also indicators at
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medium term to define a potential benefit [or not] of the combined ventilation-nutritional
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support approach, in a relatively short term of time. Biochemichal markers as prealbumin
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(prealbumin concentration increases when more than 55% of assessed protein and energy
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needs are met) and blood urea nitrogen (as a marker of protein tolerance) among with
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anthropometric parameters, as weight growth velocity, can be used to monitor nutritional
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sufficiency and can help identifying growth failure and monitoring the response to
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nutritional interventions. Finally, the clinical research should be run in the best of the
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ways as regard the definition of the primary end-points, identification of prognostically
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homogeneous classes of patients to be compared, estimate of the sample size,
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stratification and randomization of the patients, concealed analysis of final findings.
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The authors declare no conflict of interest.
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pressure [NCPAP] for preterm neonates after extubation. Cochrane Database of Systematic Reviews 2014, 9. Art. No.: CD003212. DOI: 10.1002/14651858.CD003212.pub2. [30]. Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants. Cochrane Database Syst. Rev. 2013; 3, CD000504, doi:10.1002/14651858.CD000504.pub4. [31]. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. CochraneDatabaseSyst.Rev.2014;12,CD001970,doi:10.1002/14651858.CD00197 0.pub5. [32]. Stephens BE, Gargus RA, Walden RV, Mance M, Nye J, McKinley L, et al. Fluid regimens in the first week of life may increase risk of patent ductus arteriosus in extremely low birth weight infants. J Perinatol 2008;28:123-128. [33]. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2014;12:CD000503. doi: 10.1002/14651858.CD000503.pub3. Epub 2014 Dec 4. [34]. Sweet DG, Carnielli V, Greisen G, Hallman M, Ozek E, Plavka R et al. European Association of Perinatal Medicine. European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants-2013 update. Neonatology 2013;103[4]:353-68. [35]. Kurzner SI, Garg M, Bautista DB, Bader D, Merritt RJ, Warburton D, et al: Growth failure in infants with bronchopulmonary dysplasia: nutrition and elevated resting metabolic expenditure. Pediatrics 1988; 81: 379–384. [36]. Dani C, Poggi C. Nutrition and bronchopulmonary dysplasia J Matern Fetal Neonatal Med. 2012;25 Suppl 3:37-40. [37]. Peng NH, Bachman J, Chen CH, Huang LC, Lin HC, Li TC. Energy expenditure in preterm infants during periods of environmental stress in the neonatal intensive care unit. Japan Journal of Nursing Science 2014; 11: 241–247 [38]. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T et al. ESPGHAN Committee on Nutrition. Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2010;50:85-91. [39]. Yunis KA, Oh W. Effects of intravenous glucose loading on oxygen consumption, carbon dioxide production, and resting energy expenditure in infants with bronchopulmonary dysplasia. J Pediatr 1989; 115:127-32. [40]. Aggett PJ, Haschke F, Heine W, Hernell O, Koletzko B, Launiala K et al. Comment on the content and composition of lipids in infant formulas. ESPGHAN Committee on Nutrition. Acta Paediatr Scand 1991;80:887–96. [41]. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S – 57 [42]. Lindquist S, Hernell O: Lipid digestion and absorption in early life: an update. Curr Opin Clin Nutr Metab Care 2010; 13: 314–320. [43]. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric
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Gastroenterology, Hepatology and Nutrition [ESPGHAN] and the European Society for Clinical Nutrition and Metabolism [ESPEN], Supported by the European Society of Paediatric Research [ESPR]. J Pediatr Gastroenterol Nutr 2005; 41[suppl 2]:S1–S87.
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Nutritional approach to preterm infants on noninvasive ventilation: an update
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1. Nutrition and pulmonary function are strictly related 2. A personalized nutritional approach is mandatory in infants on non invasive ventilation 3. Feeding tolerance may be impaired in ventilated infants therefore nutrition should be optimized 4. The nutritional requirements for ventilated infants are reported in the paper
S0899-9007(16)30284-2
DOI:
10.1016/j.nut.2016.12.010
Reference:
NUT 9890
To appear in:
Nutrition
Received Date: 14 October 2016 Revised Date:
29 November 2016
Accepted Date: 17 December 2016
Please cite this article as: Bozzetti V, De Angelis C, Tagliabue PE, Nutritional approach to preterm infants on non invasive ventilation: an update, Nutrition (2017), doi: 10.1016/j.nut.2016.12.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Nutritional approach to preterm infants on non invasive ventilation: an update. Valentina Bozzetti MD PhD, Chiara De Angelis MD, Paolo E. Tagliabue MD.
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Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, Monza, Italy;
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Corresponding Author: Valentina Bozzetti MD Neonatal Intensive Care Unit, MBBM Foundation, San Gerardo Hospital, via Pergolesi, 20900 Monza, Italy 0039 039 2339174 [email protected] Running title: Enteral nutrition for non-invasive ventilated infants.
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Chiara De Angelis MD email: [email protected] Paolo E Tagliabue MD email: [email protected]
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All the Authors revised the literature, wrote the paper and revised the paper approving the
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last version to be submitted
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Abstract
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Nutrition and pulmonary function in very low birth weight [VLBW] infants are strictly
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related. Preterm infants on non invasive ventilation [NIV] may have respiratory
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instability that can interfere with feeding tolerance. Moreover, feeding may impair
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pulmonary function. Those infants have nutritional requirements different than non
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ventilated infants. The main challenge of the nutritional support in such patients is to
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guarantee adequate caloric intake while avoiding episodes of feeding intolerance. This
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paper reviews the issues and the strategies of enteral feeding of preterm infants on NIV.
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Non invasive ventilation, enteral nutrition, preterm infants, growth, nutritional
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requirements.
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Background
2 Nutrition and pulmonary function in very low birth weight (VLBW) infants are strictly
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related. While maintaining an optimal pulmonary function has priority in the VLBW
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infants to secure vital functions, an adequate nutritional support plays a major role
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because a state of malnutrition not only compromises growth in general, but it has major
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adverse effects on the respiratory system. For instance, inadequate early nutrition may
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contribute to the pathogenesis of bronchopulmonary dysplasia (BPD) by hampering the
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process of lung repair in the first month of life [1]. VLBW infants, growing along the
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lower quartiles during their neonatal stay, are at higher risk for neurodevelopmental
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damage as well as chronic pulmonary complications [2]. On the other hand, infants with
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respiratory problems often experience poor growth and delayed development [3].
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As a matter of fact, infants with respiratory impairment on non-invasive ventilation
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require an adequate nutritional assessment. We therefore performed a collective and
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narrative review to analyze the issues regarding feeding preterm infants with respiratory
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impairment.
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Methods
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The following electronic databases were searched until January 2016 for published
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studies that fulfilled our criteria: Cochrane Central Register of Controlled Trials and
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PubMed (including MEDLINE). To identify potential systematic reviews/meta-analyses,
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we browsed The Cochrane Database of Systematic Reviews.
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An initial screening of the title, abstract, and keywords of every record identified was
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performed. The next step was to retrieve the full text of potentially relevant studies. The
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following search terms were used: (enteral nutrition OR enteral feeding) AND (non-
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invasive ventilation OR continuous positive pressure airway pressure). Only studies in
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english and related to infant from birth to 23 months of age were considered.
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The impact of Non-Invasive Ventilation
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Although life-saving, invasive mechanical ventilation of VLBW infants represents a
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major risk factor for the development of BPD, Ventilator-Induced Lung Injury (VILI)
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and infection [4]. VILI is reported to be associated with alveolar structural damage,
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pulmonary oedema, inflammation, and fibrosis. Mechanisms of lung injury include high
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airway pressure (barotraumas), large gas volumes (volutrauma), alveolar collapse and re-
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expansion (atelectrauma), and increased inflammation (biotrauma). In VLBW infants,
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BPD remains a leading cause of early death and morbility. Improvements in survival
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rates among such infants have led to rates of BPD of up to 60% at the lowest gestational
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ages [5].
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These concerns have prompted neonatologists to use non-invasive modes of ventilation,
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and this approach has been increasingly gaining acceptance in most NICUs. Nasal
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continuous positive airway pressure (CPAP) is an alternative to intubation and
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intermittent positive-pressure ventilation (IPPV). A meta-analysis of trials of early nasal
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CPAP versus intubation and ventilation showed that nasal CPAP reduces the risk of
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bronchopulmonary dysplasia [6]. These findings led to a more extensive utilization of
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techniques of non-invasive ventilation in the NICUs.
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Non-invasive forms of ventilation in neonates can be provided either as a single level
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support such as CPAP and High Flow Nasal Cannula (HFNC) or bilevel support such as
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Nasal Intermittent Positive Pressure Ventilation (NIPPV). Nasal intermittent positive
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pressure ventilation is a method of augmenting NCPAP by delivering ventilator breaths
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via nasal prongs. NIPPV may be synchronised with the infant's inspiration or delivered
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independently of the infant's breathing efforts, and it is usually delivered at pressures
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similar to those used during conventional ventilation. Different modes of ventilation may
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be applied non-invasively, leading to different NIPPV terminologies such as N-SIMV
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[7], N-IMV [8] and NI-PSV [9]. Various interfaces have been used to deliver NIV such
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as by face masks, nasopharyngeal and nasal interfaces. Short binasal prongs are the most
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commonly used interface for NIPPV and BiPAP [10,11].
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There is no agreement on the best technique of non-invasive ventilation. In a recent trial,
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comparing the effect of different modalities of non-invasive ventilation on the survival
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rate at 36 weeks of postmenstrual age of extremely-low-birth-weight infants without
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BPD, there was no significant difference between non-invasive respiratory support with
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nasal IPPV as compared with nasal CPAP [12].
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Feeding Issues
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It has been commonly reported that infants on non-invasive ventilation suffered of
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marked gaseous bowel distension; initially this condition was termed as the “CPAP belly
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syndrome”. This picture was described in infants that did not present abdominal
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distension at birth, but developed it after a 4-7 days course of nasal CPAP. These infants
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presented strikingly distended abdomens and visibly dilated loops. Findings on
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radiographs invariably include uniform dilatation of small-bowel and large-bowel loops
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without evidence of thickening of the bowel wall, pneumatosis or free air [13].
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Jaile et al. [13] compared 25 premature infants on nasal CPAP with 29 premature infants
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who were not on CPAP. Gaseous bowel distension due to CPAP developed in 83% of
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infants below 1000 g versus 14% of those weighing ≥1000 g. Of the 29 infants not
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receiving nasal CPAP during the study period,
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gaseous
bowel
distension,
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indisintinguishable from CPAP belly syndrome, developed in only 3 (10%). No cases of
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NEC were reported in the study; however, the sample size was too small to draw
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conclusions about NEC.
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Correlates among ventilation, mesenteric flow and gastric emptying
Several authors have reported a correlation between CPAP ventilation and mesenteric
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blood flow. Havranek et al. [14] reported that CPAP administration was associated with
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an attenuation of the postnatal increase in superior mesenteric artery blood flow velocity
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(SMA BFV) in preterm infants. [15]. Increase in SMA BFV is strictly related to feedings
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in stable infants [16] and attenuated increases in postnatal SMA BFV were associated
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with intestinal dysmotility [17] and with feeding intolerance. In a further study the
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increase in SMA BFV after feeding was measured, showing a higher increase of BFV in
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SMA from 0 to 30 min after feeding, that was greater when infants were on CPAP versus
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off CPAP. The higher increase in SMA BFV from 0 to 30 min after feeding while on
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CPAP may relate to effects of this way of ventilation on gastric emptying time. The gut
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blood flow depends on gastric emptying and feeding progression through the
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gastrointestinal tract [18-21]. The continuous positive airway pressure exerted by the
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cPAP may exert a pressure on the diaphragm thus increasing the velocity of gastric
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emptying [22].
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The clinical implications of earlier maximum postprandial SMA BFV or shorter gastric
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emptying times in this population are not known. However, a delayed gastric emptying of
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preterm infants is associated with feeding intolerance. As the way of ventilation may
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interfere with the gastrointestinal function, feeding too may impact on pulmonary
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dynamics.
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A number of Authors have speculated on the effects of the abdominal body wall and of
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the abdominal contents on the mechanics of respiration. In a study by Yu and Rolfe [23],
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pulmonary function was measured at rest and after feeding [administered as tube feeding
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by the gravity method] in infants suffering from respiratory distress syndrome (RDS) and
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in healthy infants. They used a pneumotachograph with an adaptator during spontaneous
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breathing. In infants with RDS, the respiratory rate was raised, tidal volume decreased,
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and minute ventilation increased. Compliance was reduced to one-quarter the normal
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value. Resistance was essentially unchanged, but the decrease in compliance contributed
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to a greatly increased the work of breathing. The hypothesis is that the reduction in
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functional residual capacity (FRC) after feeding might be associated with a raised
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transpulmonary pressure which causes airways closure, either de novo or to a greater
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extent than before feeding.
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There are still controversies regarding the best tolerated feeding method since the impact
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of feeding method, intermittent or continuous, upon respiratory mechanics in VLBW
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infants remains unclear. Studies in the literature are small, rather old and inconsistent.
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Blondheim et al [24] measured the dynamic respiratory function of two groups of infants
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randomly assigned to be fed intermittently or continuously. These Authors found that
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bolus gavage of 15±20 mL of milk per kg decreased tidal volume, minute ventilation, and
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dynamic compliance and increased resistance within 10 min after feeds. In a more recent
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study, Brar et al. [25] found no adverse effect of intermittent versus continuous feeding
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on respiratory system compliance and resistance, tidal volume, or FRC after feeding in
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stable full enteral fed VLBW infants thus stating that the two feeding methods were
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equivalent. Results from the two mentioned studies are conflicting (one assessing that
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bolus feeding impaired respiratory patterns, the other stating that the impact of the two
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different feeding modalities on respiratory function was the same) as the accuracy in
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pleural pressure estimation used for dynamic measurement of respiratory mechanics was
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different. In the study by Blondheim, the infants examined were VLBW preterm infants
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with RDS; Brar et al. instead evaluated at term infants. It is possible that the different
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pulmonary response to feeding might be influenced by prematurity.
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Continuous feeding infusion may result in significant higher losses of energy, mainly in
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the form of fat and protein from human milk compared with intermittent infusion. It has
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been shown that human breast milk leaves a fatty residue in the burette and in the tube at
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the end of the infusion. There is some evidence that these losses are inversely related to
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flow rates. Fat and protein loss during tube feeding could adversely affect growth
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supplying lower energy amounts as well as deprive infants of very low chain
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polyunsaturated fatty acids needed for brain and nervous system development. [26,27]
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There may be some advantages to feed in the prone position even though these benefits
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may be offset by the tendency of these infants to exhibit a higher body temperature while
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in this position [28].
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A recent Cochrane review [29] comparing the rates of gastric distension, gastrointestinal
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perforation, necrotising enterocolitis with NIPPV versus nCPAP, found no significant
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difference for any variables between the groups. So the different modalities of non-
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invasive ventilation could be used indifferently according to the gastrointestinal issues.
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Planning nutrition
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Enteral feedings are usually started in the first two to five days after birth to prime the
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gastrointestinal (GI) tract in preterm infants.
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In a systematic review, the actual volume of trophic feeds ranged from 10 to 25
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mL/kg/day and onset from day one of life onwards [30]. Early introduction of trophic
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feeds compared to fasting had a non-significant trend towards reaching full feeds earlier
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and no difference in NEC frequency as compared to fasting. In a review focusing on
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timing of introduction of nutritional enteral feeding to prevent NEC [31], early
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introduction of progressive enteral feeding (1 to 2 days of age) did not increase the risk of
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NEC, mortality or feed intolerance. Both these reviews addressed feeding questions on
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VLBW or preterm infants without stratifying the analysis among ventilated or not
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ventilated infants. So it is reasonable, when planning nutrition of non-invasive ventilated
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infants, to follow the same schedule of preterm infants without RDS about timing of
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introduction and of progression of enteral feeding.
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Providing adequate nutrition is crucial in reducing the risk and severity of RDS [32].
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High fluid was thought to increase the risk of developing BPD through the persistence of
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PDA and the occurrence of a higher fluid content in the pulmonary interstitial tissue.
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These conditions could contribute to decrease lung compliance and increase the need for
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respiratory support (i.e: oxygen and mechanical ventilation) and therefore could worsen
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the course of RDS and increase the risk of lung injury and BPD. According to a Cochrane
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review, modest restriction of fluid intake increases an early weight loss but has positive
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effect in terms of reducing PDA and NEC [33]. The risk of BPD is not significantly
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affected by water intake in any of the trials analyzed. The fluid intake therefore should be
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individualized according the fluid balance, weight changes and serum electrolyte levels
13
[34].
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Infants on ventilation may present growth delay. The etiology of this delayed growth
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performance is multifactorial including limited nutrient intake because of restricted fluid
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intake, feeding intolerance and/or prolonged parenteral nutrition, extreme prematurity,
17
and the interference with growth processes by exogenous steroids, which are often
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prescribed to enhance pulmonary compliance. Moreover, it is commonly assumed that
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infants with RDS have an increase in energy expenditure (EE) due to increase of O2
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consumption, CO2 production, rest energy expenditure and work of breathing. [35,36]
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Limitations in study designs and measurement techniques have complicated the
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interpretation of EE determinations in infants with pulmonary insufficiency. The usual
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measurement of EE requires complicated equipment, which may affect the subject’s
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environmental and behavioral pattern, making it impractical for a routine clinical
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investigation. The double labeled water (DLW) is sensitive to analytic error when used to
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measure EE in preterm infants, because preterm infants have a high growth rate, high
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body water content, and high water turnover relative to CO2 production [37].
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ESPGHAN [38] Committee on Nutrition published the nutritional requirements for
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preterm infants and reported as
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preterm infants 110-135 kcal/kg/d. Total energy needs in infants with respiratory distress
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may increase up to 150 kcal/kg per day because of increased resting energy expenditure,
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respiratory workload, activity, and insensible water losses [39]. Oxygen consumption,
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energy expenditure and work load are higher for infants with respiratory problems who
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are breathing spontaneously than for those on assisted ventilation therefore their total
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energy expenditure is strictly associated with their respiratory status.
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Based on the protein needs and nitrogen utilization, the protein intake should be at least
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3.0 g/kg/day. Protein supply needs to compensate for the accumulated protein deficit
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observed in almost all small preterm infants, and can be increased to a maximum of 4.5
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g/kg/day, depending on the magnitude of the accumulated protein deficit.
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The ESPGHAN Committee on Nutrition [40] and the expert committee convened by the
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US Life Science Research Office [39] recommended fat intake upper limits of 6.0 g/100
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kcal [40] and of 5.7 g/100 kcal [41].
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Ventilated infants with restricted fluid and feed intakes due to feeding intolerance may
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need high fat intakes to meet energy needs, for most preterm infants a reasonable range of
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fat intake is 4.8 to 6.6 g/Kg/d or 4.4 to 6.0 g/100 kcal. The medium-chain triglyceride
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content in preterm formulae, if added, should be in the range of up to 40% of the total fat
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content [40].
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Since the coefficient of fat absorption decreases with increasing chain length and
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increases with increasing number of double bonds of the fatty acid, high concentrations
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of MCTs have been used in some preterm formulas to increase the coefficient of fat
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absorption of preterm infants [42].
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Moreover, due to the high caloric density of lipids emulsion, these are a good energy
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source in clinical condition requiring fluid restriction.
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Since hyperlipidemia can cause pulmonary dysfunction, including hemorrhage, liver
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damage and coagulopathy, guidelines about lipids supplementation are prudent regarding
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the use of lipids in special disease conditions; it is recommended to adjust the delivery of
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intravenous lipids to plasma triglyceride concentrations [42].
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Non-invasive ventilated infants may experience growth delay for multiple reasons. The
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main challenge of the nutritional support in such patients is to guarantee adequate caloric
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intake while avoiding episodes of feeding intolerance.
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The knowledge about the nutritional requirements, energy expenditure and feeding
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tolerance in infants with pulmonary dysfunction is scanty and rather old; hence it is
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difficult to make universal recommendations regarding the adequate kind of nutrition and
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feeding method for premature infants with pulmonary impairment from studies
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characterized by small sample sizes and with methodological limitations.
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Moreover, the population evaluated in the studies is quite heterogeneous. The associated
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morbidities and the severity of the respiratory impairment may be very different among
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infants on non-invasive ventilation, therefore the nutritional requirements, the risk of
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feeding intolerance and consequently the impact on growth can be deeply different
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among patients.
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Future research should encompass different aspects: firstly it should adopt modern and
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reliable instrumentations for assessing the energy expenditure and specific nutrient
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requirements of infants with pulmonary impairment. So it would be possible to correlate
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the energy expenditure of the infants and subsequently personalize the energy intake.
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Secondly, it would be quite important to identify early indicators and also indicators at
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medium term to define a potential benefit [or not] of the combined ventilation-nutritional
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support approach, in a relatively short term of time. Biochemichal markers as prealbumin
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(prealbumin concentration increases when more than 55% of assessed protein and energy
14
needs are met) and blood urea nitrogen (as a marker of protein tolerance) among with
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anthropometric parameters, as weight growth velocity, can be used to monitor nutritional
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sufficiency and can help identifying growth failure and monitoring the response to
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nutritional interventions. Finally, the clinical research should be run in the best of the
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ways as regard the definition of the primary end-points, identification of prognostically
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homogeneous classes of patients to be compared, estimate of the sample size,
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stratification and randomization of the patients, concealed analysis of final findings.
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1 References
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Gastroenterology, Hepatology and Nutrition [ESPGHAN] and the European Society for Clinical Nutrition and Metabolism [ESPEN], Supported by the European Society of Paediatric Research [ESPR]. J Pediatr Gastroenterol Nutr 2005; 41[suppl 2]:S1–S87.
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Nutritional approach to preterm infants on noninvasive ventilation: an update
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1. Nutrition and pulmonary function are strictly related 2. A personalized nutritional approach is mandatory in infants on non invasive ventilation 3. Feeding tolerance may be impaired in ventilated infants therefore nutrition should be optimized 4. The nutritional requirements for ventilated infants are reported in the paper