ORIGINAL ARTICLE: GASTROENTEROLOGY

Splanchnic Oxygenation at First Enteral Feeding in

Preterm Infants: Correlation With Feeding Intolerance

Luigi Corvaglia, Silvia Martini, Barbara Battistini, yPaola Rucci, Giacomo Faldella,
and Arianna Aceti

ABSTRACT

Preterm infants are at risk of developing gastrointestinal complications such

What Is Known
as feeding intolerance and necrotizing enterocolitis. Near-infrared spec-
troscopy (NIRS) provides continuous monitoring of abdominal oxygenation
Downloaded from http://journals.lww.com/jpgn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 01/23/2021

 The establishment of enteral nutrition in preterm

(ArSO2) and could help to predict gastrointestinal complications in preterm
neonates. In this prospective observational study, ArSO2 patterns at first
enteral feed were evaluated by NIRS in 61 clinically stable preterm infants.
Splanchnic-cerebral oxygenation ratio, which is a marker of gut hypoxia,
was also calculated. ArSO2 and splanchnic-cerebral oxygenation ratio were
significantly lower both at baseline and after feeding administration in
infants who later developed feeding intolerance (n ¼ 23). NIRS could help
the early prediction of gastrointestinal complications in high-risk preterm
infants.
Key Words: feeding tolerance, near-infrared spectroscopy, splanchnic-
cerebral oxygenation ratio
(JPGN 2017;64: 550–554)
infants is often hampered by the occurrence of
feeding intolerance.
 Near-infrared spectroscopy provides a noninvasive
evaluation of mesenteric perfusion in preterm infants.
 Early identification of preterm infants at risk for feed-
ing intolerance could improve their nutritional
management.
What Is New
 This is the first report of splanchnic oxygenation
patterns following the first feed in preterm infants.
 Splanchnic oxygenation is significantly lower in
infants who will later develop feeding intolerance.
 Further studies are required to validate near-infrared

F eeding preterm infants represents a challenge for neonatolo-

gists. Early introduction of minimal enteral feeding plays a
central role in gut maturation (1) by enhancing gut hormone release
and improving gut motility. Because of gastrointestinal (GI) imma-
turity, almost 1 in 3 preterm infants develops clinical symptoms of
feeding intolerance (FI) (2), such as abdominal distension, vomit-
ing, abundant and/or bilious gastric residuals (GR), and occult or
gross bloody stools. FI can represent an early sign of necrotizing
enterocolitis (NEC) (3), which is the most severe GI complication of
prematurity. When FI occurs in preterm infants, enteral feeding is
often discontinued and this hampers the establishment of adequate
enteral nutrition. Thus, early identification of preterm infants at
Received January 25, 2016; accepted June 14, 2016.
From the Neonatology and Neonatal Intensive Care Unit, Department of
Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, and the
yDepartment of Biomedical and Neuromotor Sciences (DIBINEM),
Division of Hygiene and Biostatistics, University of Bologna, Bologna,
Italy.
Address correspondence and reprint requests to Silvia Martini, MD,
Terapia Intensiva Neonatale, Azienda Ospedaliero-Universitaria di
Bologna-Policlinicio Sant’Orsola-Malpighi, Via Massarenti 11, 40138
Bologna, Italy
(e-mail: silvia.martini4@gmail.com).
Supplemental digital content is available for this article. Direct URL
citations appear in the printed text, and links to the digital files are
provided in the HTML text of this article on the journal’s Web site
(www.jpgn.org).
www.clinicaltrials.gov registration number: NCT02383264.
The authors report no conflicts of interest.
Copyright # 2016 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0000000000001308
spectroscopy as a noninvasive tool for early predic-
tion of feeding intolerance and gastrointestinal
complications.
risk for adverse GI outcomes could improve their delicate
nutritional management.
Near-infrared spectroscopy (NIRS) provides noninvasive
continuous evaluation of regional oxygen saturation; it is widely
used for cerebral oxygenation assessment and may represent a
helpful monitoring tool for mesenteric perfusion in preterm infants
at risk for GI complications (4). In agreement with findings in
animal models (5), preterm infants who later developed NEC had
low abdominal oxygen saturation (ArSO2) values during the first
week of life (6).
At present, the use of NIRS as a monitoring tool for pre-
dicting FI in preterm infants has not been investigated extensively.
For this reason, we aimed to assess, by means of NIRS, abdominal
oxygenation in clinically stable preterm infants at the first feed and
to evaluate whether splanchnic oxygenation values differed
between preterm infants who later developed FI and those who
did not.
METHODS
Study Population
Infants admitted to the neonatal intensive care unit (NICU) of
St. Orsola-Malpighi Hospital, Bologna (Italy), between February 1,
2013 and December 31, 2014 were consecutively enrolled in this
pilot study if they fulfilled the following criteria: gestational age
(GA) 33 weeks, stable clinical conditions, and no enteral feeding

550 JPGN  Volume 64, Number 4, April 2017

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JPGN  Volume 64, Number 4, April 2017 Splanchnic Oxygenation at First Enteral Feeding in Preterm Infants

97 infants ≤33 wks admitted to the NICU during the study period

33 not eligible:
♦ IUGR: n = 21
♦ Hemodynamic instability and/or patent ductus
arteriosus: n = 7
♦ Anemia: n = 2
♦ Hypoxic-ischemic encephalopathy: n = 1
♦ Trisomy 21: n = 1
64 eligible
♦ Cerevral neoplasia: n = 1

♦ Start of enteral feeding >72 h of life: n = 2

♦ Parental consent not obtained before first feed
administration: n = 1

Enrolled
N= 61

Signs of feeding intolerance requiring

Adequate feeding tolerance
enteral feeding witholding for ≥ 24 h
N = 38
N = 23

Feeding intolerance NEC ≥ Bell’s stage IIA

n = 19 N=4

Surgery
N=4

FIGURE 1. Flow chart of the study enrollment and allocation of enrolled infants to the study groups. IUGR ¼ intrauterine growth restriction; NEC ¼
necrotizing enterocolitis; NICU ¼ neonatal intensive care unit.

before enrollment. Exclusion criteria were the following: hypoxic-
ischemic encephalopathy, multiorgan failure, major congenital
anomalies, sepsis, or other infections. Because of their possible
interference with regional tissue oxygenation, the following clinical
conditions were also considered as exclusion criteria if present at
NIRS evaluation: hemodynamic instability, hypotension, clinical
and/or ECHO signs of patent ductus arteriosus, anemia (hematocrit
30%), skin lesions at site of sensor placement, and central nervous
system diseases (eg, intraventricular hemorrhage grade 2) that
could affect cerebral oxygenation and thus interfere with the
calculation of the splanchnic-cerebral oxygenation ratio (SCOR).
Because of its association with antenatal blood flow redistribution
involving the mesenteric region, intrauterine growth restriction was
also considered an exclusion criterion.
Clinical characteristics of the enrolled infants were collected
on a specific case report form. Moreover, to assess acid-base status,
blood gas analysis parameters (ie, pH, pCO2, and base excess values)
obtained by routine capillary sampling at the time of NIRS monitor-
ing were evaluated.
Written informed consent to participate in the study was
obtained from the parents/legal guardians of each infant. The study
was conducted in conformity with the principles and regulations of
the Declaration of Helsinki. The protocol was approved by the
Ethics Committee of St. Orsola-Malpighi Hospital, Bologna, Italy
(St. Oss. No. 122/2012/U/Oss) and is registered in the Protocol
Registration System Clinical Trial.gov (ClinicalTrials.gov, Identi-
fier: NCT02383264).
First Feed Administration and Feeding
Intolerance Definition
Following our NICU nutritional protocol, enteral feeding
was started within the first 48 to 72 hours of life at volumes of 10 to

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Corvaglia et al JPGN  Volume 64, Number 4, April 2017

20 mL/kg/day. Feeds were given 3 hourly as boluses. The occur-
rence of FI was defined as the withholding of enteral feeding for
24 hours, due to the presence of at least 2 of the following signs:
abdominal distension, absent bowel sounds, persistent GR, GR
volume >2 mL/kg of body weight or greater than half the volume
of the previous feed, bilious or bloody GR, and/or bloody stools (7).
NEC stage 2 was defined according to modified Bell’s classifi-
cation (8). In relation to the development of FI during NICU
hospitalization, the enrolled infants were retrospectively divided
into 2 groups: FI versus feeding tolerance (FT).
Near-Infrared Spectroscopy Monitoring
values did not follow a normal distribution, Mann-Whitney U test
was also used to compare ArSO2 and SCOR values at each time
point between the FI and FT groups. Significantly different clinical
characteristics were included in a multivariate model to adjust for
possible confounding factors. Significance level was set at P < 0.05.
IBM SPSS Statistics version 20.0 was used for data analysis.
Graphic assessment of ArSO2 and SCOR trends over time
was obtained using locally weighted least square scatterplot
smoothing (LOWESS, Cleveland, 1979); the graph outlined with
this smoothing procedure is a fitting curve that connects adjacent
central tendency measures estimated at each time point using
local regression.

The enrolled infants underwent continuous noninvasive

monitoring of cerebral and splanchnic regional oxygenation during
the administration of the first feed. NIRS recording was performed
by means of the INVOS 5100 oximeter (Somanetics Corporation,
Troy, MI). INVOS neonatal sensors for cerebral and splanchnic
oxygenation measurement were placed on the central forehead and
under the umbilicus. In order to rule out posture-related artifacts, the
supine position was maintained and handling procedures were
minimized during the whole monitoring period.
NIRS monitoring was performed from 30 minutes before to 3
hours after the administration of the first feed. The recording was
started after achieving at least 15 minutes of stable signal. Pre-
feeding baseline values were obtained by calculating the mean
oxygenation value in the 15 minutes before feeding, whereas, to
minimize ArSO2 variability, values recorded after feeding admin-
istration were clustered into 5-minute intervals as previously
described (9). SCOR (ie, ratio between splanchnic and cerebral
oxygen saturation), which has been shown to reliably reflect
changes in mesenteric blood flow and to detect gut hypoxia
(10,11), was then calculated. Mean ArSO2 and SCOR values for
each interval were used for statistical analysis.
Statistical Analysis
Mann-Whitney U test and x2 were used to compare clinical
characteristics between the study groups (FI vs FT). Because ArSO2
RESULTS
In total, 97 preterm infants 33 weeks gestation were
admitted to our NICU during the study period; after the exclusion
of 36 infants, 61 were enrolled in the study (Fig. 1). Twenty-three
infants out of 61 later developed FI. Clinical characteristics of
infants with FI versus infants with FT are detailed in Table 1.
Abdominal oxygenation patterns at the first feed differed signifi-
cantly between FI and FT infants (Fig. 2A); specifically, infants
who developed FI had significantly lower ArSO2 values at baseline,
during the first 35 minutes after feed and from 1 hour 30 minutes
until the end of NIRS monitoring. SCOR patterns confirmed the
ArSO2 data (Fig. 2B). Median (interquartile range) and P values for
ArSO2 and SCOR at each time point are detailed in Supplemental
Digital Content, Tables 1 and 2, http://links.lww.com/MPG/
A724, respectively.
GA, birth weight (BW), and weight at first feed (FFW)
differed significantly between FI and FT infants. These 3 variables
were significantly correlated (FFW/BW r ¼ 0.984, P < 0.001; BW/
GA r ¼ 0.876, P < 0.001; FFW/GA r ¼ 0.869, P < 0.001); thus, to
avoid overadjustment bias, only GA was included in the multi-
variate model as it is strictly related to functional and anatomical GI
maturation (12). According to the multivariate model, the mean 3-
hour ArSO2 values were significantly influenced by FI status
(P ¼ 0.04) but not by GA (P ¼ 0.533). These data were also
confirmed for SCOR values (FI: P ¼ 0.03, GA: P ¼ 0.895).

TABLE 1. Characteristics of infants with feeding intolerance versus adequate feeding tolerance

Characteristics FI (n ¼ 23) FT (n ¼ 38) P

Gestational age, weeks (median, IQR) 29.6 (27.6–31) 31.4 (30.4–32.8) 0.011
Birth weight, g (median, IQR) 1252 (920–1616) 1611 (1307–1835) 0.013
Weight at first feed, g (median, IQR) 1140 (875–1559) 1555 (1190–1698) 0.012
Males, n (%) 10 (43%) 19 (50%) 0.621
Twins, n (%) 11 (48%) 20 (53%) 0.716
Mode of delivery, n (%) 0.558
Vaginal delivery 5 (22%) 6 (16%)
Caesarean section 18 (78%) 32 (84%)
Apgar score at 5’ (median, IQR) 8 (8–9) 8 (8–9) 0.662
Acid-base status at first feed:
pH (median, IQR) 7.34 (7.33–7.36) 7.34 (7.32–7.35) 0.596
PaCO2, mmHg (median, IQR) 40.9 (39.3–42) 41 (39.1–43) 0.674
Base deficit (median, IQR) 2.9 (2.5–3.1) 2.7 (2.3–3.2) 0.689
Hematocrit at first feed % (median, IQR) 50.3 (46.1–51.2) 51.3 (46.8–52.8) 0.857
Type of feeding, n (%) 0.561
Human milk 19 (83%) 29 (76%)
Preterm formula 4 (17%) 9 (24%)
Time to achieve FEF, days (median, IQR) 25 (21–33) 14 (10–21) <0.001
Necrotizing enterocolitis, n (%) 4 (17%) 0 (%) <0.001

FEF ¼ full enteral feeding; FI ¼ feeding intolerance; FT ¼ feeding tolerance; IQR ¼ interquartile range.

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JPGN  Volume 64, Number 4, April 2017 Splanchnic Oxygenation at First Enteral Feeding in Preterm Infants

A B
Feeding
100 1.00 intolerance

SCOR (splanchnic-cerebral oxygen ratio)

No
Yes

80 0.80

0.60
ArSO2 (%)

60

0.40
40

0.20

20
0
* * * * *P <0.05

0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
e

e
lin

lin
se

se
Time (minutes) Time (minutes)
Ba

Ba
FIGURE 2. Abdominal oxygen saturation (ArSO2) (A) and splanchnic-cerebral oxygenation ratio (B) patterns at first feed administration in infants
who later developed feeding intolerance (solid line) and infants who did not (dotted line). SCOR ¼ splanchnic-cerebral oxygenation ratio.

DISCUSSION (20), possibly contributing to NEC development (21). The potential

The present study shows that abdominal oxygenation at first influence of these factors on the study results was ruled out, because
feed is lower in preterm infants who later develop FI compared with anemic infants were not included in the present study and no
those with adequate FT. In healthy preterm infants, it is known that difference in hematocrit values or in the acid-base status was
administration of the first feed increases postprandial blood flow in observed between the 2 groups.
the superior mesenteric artery (SMA). An impairment of postfeed Infants in the FI group had a significantly lower GA, which is
SMA flow has been observed by Doppler ultrasound in preterm a known risk factor for FI development (22). For this reason, to rule
infants who later developed FI or NEC (13,14). Doppler assess- out a possible effect of GA on abdominal oxygenation, a multi-
ment, however, needs trained personnel and does not allow con- variate analysis was performed, which showed that the observed
tinuous monitoring; by contrast, NIRS provides noninvasive, ArSO2 values were significantly related to FI, but not to GA.
continuous monitoring of regional tissue oxygenation and, for this According to the results of the present study, FI infants had
reason, it is increasingly used to evaluate mesenteric perfusion in lower SCOR values both at baseline and after the first feed,
preterm infants with GI complications (10,15,16). An association compared with FT infants. As cerebral tissue oxygenation is
between splanchnic oxygenation, FI, and NEC was first reported by relatively stable, SCOR helps to identify abnormal processes
Cortez et al (17) in a small number of preterm infants evaluated affecting the gut (11), and is effective in detecting neonatal
during the first 2 weeks of life. Infants with FI had persistently splanchnic ischemia (10). We might speculate that the lower
lower ArSO2 values with maintained variability, whereas NEC splanchnic oxygenation observed in infants with FI could be related
development was associated with extremely low ArSO2 values, to a specific impairment of mesenteric hemodynamics, or simply
loss of variability, and signal dropout. Low ArSO2 values in preterm reflect poor intestinal growth and perfusion during fetal life, both of
infants who developed NEC were also observed by Patel et al (6) in which could lead to gut hypoxia and predispose these infants to
a larger cohort. In Patel’s study, however, NIRS monitoring was GI complications.
limited to 5-minute intervals recorded before, during, and 1 hour A possible limitation of the present study is that the assess-
after feeds. Therefore, ArSO2 changes occurring out of these ment of ArSO2 in response to enteral feeds was limited to the first
intervals were not detected. In addition, ArSO2 values were enteral feed, and was not evaluated over time or shortly before FI or
obtained over the first 2 weeks of life; thus, the predictive value NEC development; this might have helped to identify ArSO2
of early splanchnic oxygenation in identifying preterm infants at patterns predictive of GI complications.
high risk of NEC was not assessed. The results of the present study prompt further research
In a recent study, Dani et al (18) did not find any correlation aimed at validating NIRS as a noninvasive bedside tool for early
between splanchnic oxygenation and FI development in preterm identification of preterm infants at risk of development of FI and
infants on continuous feeding. The study, however, did not evaluate GI complications.
specifically the first enteral feed, as it was performed over a
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