after birth , the neonate must transition to the gastrointestinal system as the primary source of nutrition .
in premature newborns , the gastrointestinal system and other organ systems in the body are underdeveloped .
this is a challenge because the neonatologist must assess the function of the intestine for management of enteral feeding .
much of the knowledge about the physiology of the intestines in neonates is derived and subsequently inferred from experimental animal models .
clinical methods to assess intestinal function include abdominal distension , aspiration of gastric residuals ( gr ) , bowel auscultation , and abdominal x - ray .
however , recently two noninvasive technologies have demonstrated potential to assess intestinal function in the neonatal intensive care unit ( nicu ) : transabdominal ultrasonography ( us ) and near - infrared spectroscopy ( nirs ) .
different modalities of transabdominal us have been utilized by some investigators for assessment of necrotizing enterocolitis ( nec ) [ 813 ] .
for example , studies have found that us is more sensitive than x - rays in detecting intramural gas , portal venous gas , free peritoneal gas and free peritoneal fluid [ 1317 ] .
color doppler us of the abdominal wall is more accurate than clinical examination and x - ray in detecting bowel necrosis . in principle , transabdominal us allows the visualization of peristaltic movements .
the bowel walls are visible as multiple white echoic lines in a darker hypoechoic background of peritoneum .
peristaltic contractions appear as  wormlike  movements of the bowel wall . in a recent publication , richburg and kim
duodenojejunal manometry , another measure of small intestinal motility , has previously been found to be a sensitive predictor of feeding intolerance in preterm infants . however , this method is more invasive than transabdominal ultrasonography , and requires more specialized equipment and operator training .
near - infrared spectroscopy ( nirs ) is a noninvasive technology available to obtain in vivo , real time , portable , and continuous measurement of tissue oxygen saturation of hemoglobin ( sto2 ) .
nirs exploits the different absorptive properties of deoxyhemoglobin , oxyhemoglobin , and underlying tissue to measure sto2 .
physiologically , sto2 is a measure of a combination of oxygen saturation in venous , arterial , and capillary blood .
thus , sto2 is dependent on the regional delivery and consumption of oxygen in the tissues .
while us may be operator dependent and assesses function at the time of the intervention , it remains the current gold standard to directly visualize motility .
the advantage of nirs is that it can be used without an operator over relatively long time intervals .
our group recently studied continuous cerebral sto2 over 24 h to determine the hemodynamic effects of umbilical cord milking in preterm neonates .
although blood flow through the superior mesenteric artery ( sma ) , was found to correlate with sto2 measurements , no study to date has validated splanchnic nirs measurements with a local imaging method that measures intestinal function . correlating a method of continuous nirs monitoring with a validated functional imaging technique
the objective of our study is to explore the relationship between us derived assessment of motility and levels of sto2 derived from nirs instrumentation .
this pilot study was conducted in the level iii neonatal intensive care unit ( nicu ) at sharp mary birch hospital for women and newborns in san diego , california between december 2013 and may 2014 .
the data was collected as part of the validation study of the fore - sight ii nirs tissue oximeter monitor for splanchnic sto2 .
the study was approved by the sharp healthcare institutional review board and registered on clinical trials.gov ( nct02017652 ) .
inclusion criteria were as follows : ( i ) gestational age greater than 32 weeks ; ( ii ) weight of less than 5000 g ; and ( iii ) umbilical venous catheterization to obtain a venous partial pressure of oxygen for device calibration as part of a multicenter trial ( currently ongoing ) .
a gestational age of 32 weeks was chosen to enroll those that would be large and well enough to have nirs monitoring but also require a nicu admission .
no infants who required any significant respiratory support ( mechanical ventilation or nasal ventilation ) , or cardiac inotropes were included .
a venous blood sample from the umbilical venous catheter was drawn for the validation study of the nirs technology .
exclusion criteria were perinatal asphyxia events , intraventricular hemorrhage , vascular or coagulation disorders , congenital anomalies , or a history of nec . upon enrollment ,
bowel ultrasound scans were performed using a vivid e9 ( ge healthcare , wauwatosa , wisconsin ) system and an 11 mhz linear probe .
the transducer was placed on the left , middle and right abdomen ( figure 1a ) , and the peristaltic movements of the intestine were observed for 10 s at each location . immediately after the ultrasound scan , a nirs infrared probe ( casmed , fore - sight ii , branford , ct , usa ) was placed on the left lower quadrant of the abdomen ( figure 1b ) .
splanchnic sto2 data was recorded into a laptop every 2 s for 24 h. the blinded ultrasonographer ( da ) classified the babies into the respective motility levels , based on the observed peristaltic activity .
image features of a peristaltic movement of the bowel wall included rotational movement , displacement or sudden disappearance / reappearance of the echogenic bowel over 30 s ( 3 consecutive 10-s clips ) . to be considered a peristaltic activity , the movement must be localized to a small section of the image .
( i.e. no , low , normal , hyperactive ) , were reduced to two distinct categories of visible levels of motility .
the lower level categories ( i.e.  no  ,  low  ) were merged into a single  no / low  level , while the upper two categories ( i.e.  normal  ,  hyperactive  ) were merged into a  normal / hyperactive  category .
the no / low category was assigned to subjects with minimal or no motility ( 02 peristaltic movements ) observed in any 10-s image .
an alternative normal / hyperactive category was assigned to a subject with multiple peristaltic movements ( 3 peristaltic movements ) in any 10-s image .
movement of echogenic lines that are not localized to a small region of the image , are considered artifacts due to movement of the baby , movement of the us probe , or displacement of the abdominal contents ( for example due to breathing ) .
doppler ultrasonography of the superior mesenteric artery   was performed using an 8 mhz phased array transducer to measure the peak systolic velocity ( vsystole ) and end diastolic velocity ( vdiastole ) .
the arterial resistivity index was determined by using the following relation : for analysis of the recorded nirs measurements , the data was initially smoothed with a moving - window of 20 s. for each 24-h dataset , a representative distribution of measurements was generated from a uniform random sampling of multiple overlapping 4-min intervals , such that the average difference between the centers of the intervals was 1 min .
figure 1c illustrates an 8-min interval of sto2 samples with two 4-min linear fits highlighted in red .
a linear fit was performed for each of the randomly selected 4-min intervals . for visualizing the distributional properties of the representative measurements ,
the average sto2 ( i.e. bias values of the linear fits ) of all selected 4-min intervals over the 24 h were summarized into a single box plot .
this was repeated for all cases , for a total of 19 boxplots . to measure the variability of the 4-min linear trends ,
the residual errors are deviations from the line - of - best fit for each 4-min interval .
the averages of the residual errors for each 4-min interval over the 24 h were summarized into box plots .
for further analysis , the distributions of average sto2 and respective residual errors were normalized to zero mean and unit standard deviation .
a multivariate linear regression model   was created using the following factors as training and test inputs : means , residual errors , and pairwise products . a nonlinear variant ( 3-node single hidden - layer neural network )   of the regression model
two sets of box plots were created for the global linear and non - linear regression models . as this was a pilot study without prior data comparing nirs to us , a convenience sample size of 19 subjects was obtained . for initial exploratory analysis purposes ,
the differences between the sto2 distributions for the no / low versus normal / hyperactive motility assignments were assessed using multivariate analysis of variance ( manova ) techniques . for the results reported herein , the lm ( ) and anova ( ) commands in r (
; 2015 - 06 - 18 ) , were utilized for generating the linear fits and comparison of the means and medians of the respective distributions .
the nnet ( ) command in r ( nnet package ) was utilized for generating the nonlinear variant of the linear regression model .
the nutritional intake was recorded at the bedside over the course of 24 h and additional data relevant to the study ( maternal and infant characteristics ) were collected from the patient s electronic medical record and managed using redcap database application ( redcap software v5.7.1 2014 vanderbilt university ) .
mann - whitney u , chi - squared , or t tests were used for data analysis where appropriate .
four patients were excluded from the study , 2 because of inability to obtain a venous blood gas from the uvc lines , and 2 due to insufficient data . after undergoing abdominal ultrasound imaging , 8 subjects had negligible peristaltic movements visible on bowel ultrasonography and were classified into the no / low group .
differences in gestational age and day of life at enrollment were not significant between the 2 categories .
birthweight was higher in the normal / hyperactive group and the mean magnesium levels were higher in the no / low group ; however , these results were not statistically significant ( p=0.11 and p=0.09 , respectively ) .
the no / low group had a higher incidence of abdominal distention ( 2 vs. 0 ; p = na ) , gastric residuals ( 7 vs. 4 ; p=0.03 ) , and gastric residual volume ( 2.03 ml vs. 0.87 ml ; p=0.06 ) .
the no / low group had a lower volume of enteral nutrition during the duration of the study ( 13 ml vs. 98 ml ; p=0.02 ) .
table 3 summarizes the data obtained from the ultrasonography measurements . on all three 10-s ultrasound images ,
the no / low category had an average of 1.91.3 peristaltic movements and the normal / hyperactive group had an average of 9.22.2 peristaltic movements .
the peak systolic velocity through the superior mesenteric artery was higher in the normal / hyperactive ( 77.26.3 cm / s vs. 58.58.1 cm / s ; p=0.04 ) .
neonates who were classified as having normal / hyperactive motility had on average higher sto2 over 24 h ( figure 3a ) than those classified as having no / low motility ( 72.34.4 vs. 65.57.9 , p=0.03 , f=5.65 )
. on average , no / low motility neonates also had higher variability , or deviations ( i.e. , residual errors ) from the 4-min linear fits as shown in figure 3b . as a univariate factor ,
the difference in the residual error ( goodness - of - fit ) was not considered statistically significant ( 1.480.26 vs. 1.730.58 , p=0.213 , f=1.67 ) .
the global linear regression models showed a higher level of separation between the groups ( 0.470.26 vs. 0.240.33 , p=0.0001 , f=27.4 ) , as illustrated in figure 3c .
the non - linear variant of the regression model showed the highest level of separation between the 2 groups ( 0.680.24 vs. 0.490.53 , p=0.0001 , f=41.9 ) , as illustrated in figure 3d .
emerging noninvasive continuous monitoring techniques , such as cerebral nirs ( cerebral sto2 ) and electrocardiography ( cardiac output , stroke volume ) , have been utilized by our group to augment continuous recording of more common vital signs , such as heart rate , blood pressure , mean arterial pressure , and arterial oxygen saturation ( spo2 ) .
previous studies by other groups developed nirs - based methods for describing splanchnic sto2 characteristics in relation to : cerebral sto2 , superior mesenteric artery flow , blood transfusions , hyperemia after feeds , apneic episodes , feeding intolerance , patent ductus arteriosus   and necrotizing enterocolitis . the methods of nirs data recording , statistical analysis , and instrumentation vary widely among these studies . to date
, no other study has validated splanchnic nirs with a functional medical imaging technique which measures intestinal function , such as the one described by richburg et al . .
in this pilot study , we were successful in describing a relationship between this method of medical imaging and nirs .
this study found that higher motility levels correspond to higher average splanchnic sto2 over a 24-h period .
we attribute this finding to increased delivery of oxygenated arterial blood in the normal / hyperactive group , as observed by doppler us of the sma ( insert results ) . although peristaltic contractions of the smooth muscle cells result in increased oxygen consumption ( which would decrease sto2 ) , some metabolic products of peristaltic activity ( such as adenosine ) are powerful vasodilators that increase arterial blood flow by as much as a factor of 4
. however , motility and blood flow are dependent on many other factors : gestational age , postnatal age , time after administration of feeds ( fed / unfed state ) , and overall maturation .
the gestational age and postnatal age did not differ significantly between the 2 comparison groups .
the total volume of feeds over the 24 h of monitoring was significantly higher in the normal / hyperactive group ( results ) , which suggests that infants in the normal / hyperactive group had better overall intestinal function . to identify normal and abnormal intestinal function and development ,
larger stratified studies are needed to further describe the gestational postnatal age and postprandial evolution of motility and circulation .
multivariate regression models using a combination of sto2 and goodness - of - fit , displayed the highest degree of separation between the 2 groups . in the normal / hyperactive group , 2-s measurements more consistently increased ( positive slope ) , decreased ( negative slope ) , or stayed the same value ( zero slope ) throughout 4-min sample intervals .
overall , the regression models indicate that at higher sto2 levels , the 4-min trends tend to be more linear and less random .
we attribute the less random nature to more functional auto - regulatory mechanisms in the intestinal microcirculation .
one of the future applications of this study lies in the decision to advance or delay enteral feeds in preterm neonates .
feeding protocols are generally based on the gestational age ( ga ) and birthweight of neonates and subsequent trial and error of tolerance [ 37 ] .
one method available to estimate tolerance of feeds is the collection of gastric residual ( gr ) aspirates . in the present study ,
however , even the presence of grs is often not a sufficient reason to decrease or interrupt enteral feeds , as maintaining feeding may improve gastrointestinal maturation and feeding tolerance .
clinicians consider gastric residuals suspect if they are > 3050% of the previous feed or bilious - stained .
our findings that multivariate linear regression models of continuous sto2 measurements correlate closely with us motility measurements suggest that nirs may be also used for gauging feeding readiness .
another future application of our results is in the early detection of neonates at high risk of nec , which often occurs unpredictably , with subsequent high morbidity and mortality .
patel et al . found that infants with nec have a higher variability of sto2 .
the variability of sto2 measurements suggests an impairment of auto - regulation of blood flow .
this is consistent with our finding that infants with higher intestinal function tend to adhere to a more linear trend of 4-min measurement intervals .
this is also consistent with the study by downard et al . , which described a discontinuous  stop - and - go pattern  of flow in venules of rats with induced nec .
in this context , our study suggests an alternative analysis of sto2 data that is potentially useful for future nec studies .
the sample included relatively mature preterm babies of gestational age > 32 weeks , and the timing of the scans were not predefined .
this was an exploratory study to describe the general correspondence between 2 techniques which are not currently used in our nicu .
more work is needed to apply our results to neonates who may benefit the most from this type of noninvasive monitoring .
movement of the baby , movement of abdominal contents due to contraction of the diaphragm during breathing , movement of the ultrasound probe , and presence of small amounts of air can create artifacts that affect the quality of the images .
nirs instrumentation is also subject to motion artifacts and light interference which limit the accuracy of nirs measurements .
this is the first study to demonstrate an association between nirs - based sto2 measurements and peristaltic activity visualized by ultrasound imaging .
in addition to continuously monitoring splanchnic sto2 level , nirs may offer a continuous , noninvasive method to indirectly assess intestinal motility and function .
future research will focus on the applicability of the methods and results demonstrated in this study for predicting tolerance to feeds , advancing or withholding enteral feeding , and early detection of necrotizing enterocolitis .
 backgroundnear - infrared spectroscopy ( nirs ) has the potential to continuously and noninvasively monitor intestinal function 
 . this technology may be valuable because among neonates , intestinal maturity is highly variable and difficult to assess based solely on clinical signs . 
 the aim of this study was to determine if there is an association between nirs - based sto2 measurements and peristaltic activity assessed by transabdominal ultrasonography ( us).material / methodsnineteen neonates of gestational age > 32 weeks were categorized according to  no / low  versus  normal / hyperactive  motility levels , based on blinded us scan results . 
 sto2 was recorded every 2 s for 24 h , following the ultrasound recording . 
 differences between the resulting estimates of average sto2 ( bias of fits ) and goodness - of - fit ( residuals ) were evaluated.resultsnewborns with normal / hyperactive motility had higher mean sto2 than newborns with no / low motility ( 72.34.4 vs. 65.57.9 , p<0.05 , f=5.65 ) . 
 residual errors were not significantly different between the 2 groups ( p=0.213 , f=0.213 ) . 
 a multivariate linear regression model using the means , residuals , and pairwise products of both , demonstrated more significant separation ( 0.470.26 vs. 0.240.33 , p<0.01 , f=27.4 ) . a non - linear variant of the multivariate linear regression model demonstrated greatest separation ( 0.680.24 vs. 0.490.53 , p<0.01 
 , f=41.9).conclusionsthis is the first study to demonstrate an association between nirs - based sto2 measurements and peristaltic activity visualized by ultrasound imaging . 
 nirs may offer a continuous , noninvasive method to assess motility . 
 this may have significant implications in premature infants at risk for feeding intolerance or necrotizing enterocolitis . 
Background
Material and Methods
Results
Discussion
Conclusions