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Original Investigation | Pediatrics

Association of Bolus Feeding With Splanchnic and Cerebral Oxygen UtilizationEfficiency Among Premature Infants With Anemia and After Blood TransfusionKiran Kumar Balegar V, FRACP, DM; Madhuka Jayawardhana, PhD; Andrew J. Martin, PhD; Philip de Chazal, PhD; Ralph K. H. Nanan, Dr Med Habil

Abstract

IMPORTANCE The pathogenesis of transfusion-associated necrotizing enterocolitis remains elusive.Splanchnic hypoperfusion associated with packed red blood cell transfusion (PRBCT) and feedinghas been implicated, but studies of splanchnic tissue oxygenation with respect to feeding plus PRBCTare lacking.

OBJECTIVE To investigate the oxygen utilization efficiency of preterm gut and brain challenged withbolus feeding during anemia and after transfusion using near-infrared spectroscopy.

DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study conducted from September1, 2014, to November 30, 2016, at a tertiary neonatal intensive care unit included 25hemodynamically stable infants with gestational age less than 32 weeks, birth weight less than 1500g, and postmenstrual age younger than 37 weeks. Data analysis was performed from August 1, 2017,to October 31, 2018.

EXPOSURES Infants received PRBCT (15 mL/kg for 4 hours) and at least 120 mL/kg daily of secondhourly bolus feedings.

MAIN OUTCOMES AND MEASURES Splanchnic fractional tissue oxygen extraction (FTOEs) andcerebral fractional tissue oxygen extraction (FTOEc) measures were made during 75-minute feedingcycles that comprised a 15-minute preprandial feeding phase (FP0) and 4 contiguous 15-minutepostprandial feeding phases (FP1, FP2, FP3, and FP4; each 15 minutes long). The intraindividualcomparisons of feeding-related changes were evaluated during the pretransfusion epoch (TE0: 4hours before onset of transfusion) and 3 TEs after transfusion (TE1: first 8 hours after PRBCTcompletion; TE2: 9-16 hours after PRBCT completion; and TE3: 17-24 hours after PRBCT completion).

RESULTS Of 25 enrolled infants (13 [52%] female; median birth weight, 949 g [interquartile range{IQR}, 780-1100 g]; median gestational age, 26.9 weeks [IQR, 25.9-28.6 weeks]; median enrollmentweight, 1670 g [IQR, 1357-1937 g]; and median postmenstrual age, 34 weeks [IQR, 32.9-35 weeks]),1 infant was excluded because of corrupted near-infrared spectroscopy data. No overall associationwas found between FTOEs and FPs in a multivariable repeated-measures model that accounted fortransfusion epochs (primary analysis approach) (FP0: mean estimate, 11.64; 95% CI, 9.55-13.73; FP1:mean estimate, 12.02; 95% CI, 9.92-14.11; FP2: mean estimate, 12.77; 95% CI, 10.68-14.87; FP3: meanestimate, 12.54; 95% CI, 10.45-14.64; FP4: mean estimate, 12.98; 95% CI, 10.89-15.08; P = .16 for theFP association). However exploratory analyses of postprandial changes in FTOEs undertaken foreach transfusion epoch separately found evidence of increased postprandial FTOEs during TE1 (mean[SD] FTOEs, 10.55 [5.5] at FP0 vs 13.21 [5.96] at FP4, P = .046). The primary and exploratory analysesfound no association between FTOEc and feeding phases, suggesting that cerebral oxygenation maybe protected.

(continued)

Key PointsQuestion Is there an association

between feeding and splanchnic and/or

cerebral oxygen utilization efficiency

during anemia and/or after packed red

blood cell transfusion?

Findings In this cohort study of 25

hemodynamically stable, bolus-fed

preterm infants who received packed

red blood cell transfusions, splanchnic

fractional tissue oxygen extraction was

adversely associated with feedings in

the immediate (first 8 hours)

posttransfusion period. Cerebral

fractional tissue oxygen extraction was

protected during the anemia and

posttransfusion periods.

Meaning The findings suggest that

enteral feeding may be associated with

gut ischemia and potentially

transfusion-associated necrotizing

enterocolitis and reiterate cerebral

autoregulation in this context.

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2020;3(2):e200149. doi:10.1001/jamanetworkopen.2020.0149 (Reprinted) February 28, 2020 1/14

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Abstract (continued)

CONCLUSIONS AND RELEVANCE The findings suggest that enteral feeding may be associated withgut ischemia and potentially transfusion-associated necrotizing enterocolitis. The postprandialchanges in FTOEs appear to warrant further investigation in larger randomized studies.

JAMA Network Open. 2020;3(2):e200149. doi:10.1001/jamanetworkopen.2020.0149

Introduction

Several studies1-7 suggest a temporal association between packed red blood cell transfusion (PRBCT)in the 48 to 72 hours preceding PRBCT and the development of necrotizing enterocolitis (NEC) inlow-birth-weight infants. Compared with classic NEC, transfusion-associated NEC (TANEC) cases aremore severe,2 with higher rates of surgical intervention6 and mortality.1 In general, TANEC hasdelayed postnatal age at onset, and infants tend to be of lower gestational age and birth weight, tobe sicker on the first days of life, and to have higher odds of having patent ductus arteriosus(PDA).1-3,5,6,8-13 Cases of TANEC are reported to be associated with transfusion of red blood cellsstored for a longer period and transfusion given for significant anemia.11 Although the pathogenesisof TANEC is unclear, a proposed hypothesis includes transfusion-induced splanchnic hypoperfusion,further exacerbated by feeding5,14,15 in the context of anemia,15-17 and vulnerable splanchnicmicrocirculation in premature infants.18 Some clinical studies2,6,7 have found variable resultsregarding the role of feeding in infants with TANEC, with some showing no benefit of withholdingfeeding from infants during the transfusion period, whereas others3-5,12 suggest an associationbetween feeding and TANEC. As a result, feeding practices during the peritransfusion period arevariable in different neonatal intensive care units.19,20 Physiologic studies in animals16,21 and pretermnewborns15,22 on the association of anemia and transfusion with postprandial mesenteric blood flowand/or tissue oxygen levels are limited. Prospective physiologic data using near-infraredspectroscopy (NIRS) to evaluate the interplay between splanchnic oxygen delivery and consumptionare necessary to better understand the oxygen utilization efficiency of preterm gut challenged withbolus feeding during anemia and after transfusion.

Although cerebral autoregulation and its mechanism in preterm infants have been extensivelyinvestigated,23 there is a paucity of studies evaluating the dynamic equilibrium between cerebraloxygenation consumption and supply during feeding and transfusion, and the available studies17,24

have produced variable results.The current study was conducted to evaluate the association of bolus enteral feeding on

splanchnic and cerebral tissue bed oxygenation in anemia and after PRBCT using NIRS and to assessthe duration of any association after transfusion. We hypothesized that splanchnic tissueoxygenation would be reduced after feedings in infants with anemic status and would be worserather than improved after PRBCT. We also hypothesized that cerebral oxygenation would beunaffected because of its autoregulatory capacity.

Methods

This prospective cohort study was conducted in the tertiary neonatal intensive care unit at NepeanHospital, Sydney, Australia, from September 1, 2014, to November 30, 2016. Data analysis wasperformed from August 1, 2017, to October 31, 2018. Eligibility criteria were as follows: gestationalage less than 32 weeks, birth weight less than 1500 g, postmenstrual age younger than 37 weeks,tolerating total daily feeding volume at least 120 mL/kg, and hemodynamically stable and receivingelective PRBCT to treat anemia of prematurity. Infants with NEC (current or previous); feedingintolerance (defined as the treating clinical team’s decision to withhold feedings or withhold gradingup of feedings for at least 12 hours); sepsis (defined as the treating clinical team’s decision to

JAMA Network Open | Pediatrics Bolus Feeding and Oxygen Use Efficiency in Premature Infants With Anemia and After Blood Transfusion




commence antibiotic treatment); PRBCT in the previous 72 hours; PDA or its treatment withibuprofen, indomethacin, or surgery in the previous 72 hours; and/or congenital gastrointestinal,complex cardiac, or lethal anomalies were excluded. An infant was enrolled only once even whenreceiving multiple transfusions. For pragmatic reasons, enrollment occurred only when PRBCT wasinitiated during normal business hours (8 AM to 5 PM weekdays). A pragmatic sample size of 25 wasselected to facilitate reasonable enrollment based on the number of potentially eligible infantstypically admitted to the neonatal intensive care unit and the rate of transfusion. Consecutive infantswho satisfied these criteria were enrolled after a written informed parental consent was obtained bythe chief investigator (K.K.B.V.) or one of the designated officers. All data were deidentified. Thestudy protocol, including parental consent, was approved by the Nepean Blue Mountain Local HealthCommittee. This study followed the Strengthening the Reporting of Observational Studies inEpidemiology (STROBE) reporting guideline.

Transfusion and Bolus FeedingsOnce a clinical decision was made for transfusion, the study period extended from 4 hours before thePRBCT until 24 hours after its completion. The decision to administer PRBCT was made by theattending neonatal team composed of neonatologists (including one of us [K.K.B.V.]), neonataltrainees, and neonatal nurses independent of the study. No formal protocol existed regarding thehemoglobin threshold at which infants received a PRBCT. The decision to transfuse was made basedon a combination of clinical factors in addition to low hemoglobin level (eg, respiratory support,increasing desaturations, poor growth, gestation, and reticulocyte response). Infants receivedPRBCT at 15 mL/kg for 4 hours without furosemide. Type (breast milk vs formula) and volume offeeding were determined by the clinical team independent of the study but remained the sameduring the entire study period. Only infants who tolerated a reasonable feeding volume (defined as�120 mL/kg daily) were enrolled because of concerns that feeding intolerance attributable to otherreasons (eg, premature sluggish gut or NEC) may confound splanchnic oxygenation independent offeeding. For standardization across enrolled infants during the study period, the second hourlyaliquots of total daily feeding volume were given as bolus via gastric tube at a constant rate using asyringe pump. The rate was chosen as 120 mL per hour based on the mean rate of gavage feeding in acohort of 30 preterm infants. A standardized rate of bolus feedings was given to avoid potentialfeeding intolerance (such as vomiting or regurgitation) because of variation in the rate of the bolus byother methods, such as gavage feedings or hand push.

NIRS Monitoring and FTOE CalculationThe NIRS measures oxygen saturation in the tissue bed approximately 1 to 2 cm beneath the sensorand displays it as regional tissue oxygen saturation (StO2) on a scale from 15% to 95%.25-32 Throughthe simultaneous monitoring of arterial oxygen saturation as measured by pulse oximetry (SpO2) andStO2, FTOE was calculated as follows: FTOE = ([SpO2 – StO2] × 100/[SpO2]). The FTOE indicates theefficiency of oxygen utilization and is determined by oxygen consumption in the context of prevailingoxygen delivery (FTOE = [oxygen consumption/oxygen delivery]). FTOEc has been studied inpreterm infants as a surrogate measure of the adequacy of consumption vs delivery. An increase inFTOE indicates inefficient tissue oxygen utilization owing to consumption being out of proportion todelivery.33,34 Similarly, a decrease in FTOE indicates efficient tissue oxygen utilization with deliverybeing adequate for tissue needs. A change in FTOE rather than absolute values is meaningful.

During the entire study period, a continuous prospective evaluation of StO2 was performedusing a 4-wavelength NIRS cerebral and splanchnic tissue monitor (FORE-SIGHT absolute cerebraloximeter, CAS Medical Systems Inc) placed on the lower quadrant of the abdomen just below theumbilicus28,35 to obtain splanchnic StO2 and a second neonatal sensor placed over the temporalregion of the head to obtain cerebral StO2. SpO2 was monitored using the Masimo Radical-7 monitor(Radical-7 Pulse CO-Oximeter, Masimo Corp) for concurrent measurement of arterial oxygensaturation. For infants who needed supplemental oxygen, fraction of inspired oxygen was adjusted




http://www.equator-network.org/reporting-guidelines/strobe/

to a target SpO2 of 91% to 95%, as per the unit protocol. Skin integrity was closely monitored bylifting the sensors and inspecting the skin every 6 hours during care tasks (eg, handling of neonatesfor a diaper change, eye care, and change of posture). The start and end times of the study, as well asvarious events (transfusion, feedings, and care tasks), were electronically annotated in real time. Asa backup, these events were also recorded on a hard copy datasheet. Other demographicinformation (Table 1) was also collected.

Data ProcessingThe StO2 and SpO2 data were downloaded as an analog output at a sampling rate of 1000 Hz andaligned along the time axis in LabChart reader format (.adicht files) using a PowerLab data acquisitionsystem36 (ADInstruments). The .adicht files were converted into .mat file format using a simplePython script (Python, version 3.7.337) and resampled at 1 Hz for faster processing. Data that couldnot be physiologically explained (eg, absence of variability35 or a 30% step change in StO2 between 2subsequent data points for StO2

38) were removed. Data during the care tasks were presumed to beartifactual for 2 reasons. First, NIRS sensors were lifted for inspection of underlying skin during thisperiod. Second, infants underwent diaper change, oral care, change of position, and other events

Table 1. Main Clinical Characteristics of the Study Participantsa

Characteristic Finding (n = 25)Baseline characteristics

Gestational age, median (IQR), wk 26.9 (25.9-28.6)

Birth weight, median (IQR), g 949 (780-1100)

Female 13 (52)

Restricted umbilical arterial flows onantenatal Doppler studies

2 (8)

Small for gestational age 3 (12)

Enrollment characteristics

Postmenstrual age, median (IQR), wk 34 (32.9-35)

Postnatal age, median (IQR), d 42 (27-59)

Weight, median (IQR), g 1670 (1357-1937)

Breathing support

None 5 (20)

Continuous positive airway pressure 10 (40)

High-flow nasal cannula 8 (32)

Low-flow oxygen 2 (8)

Daily feed intake, median (IQR), mL/kg 160 (150-160)

Nature of feedings

Breast milk without fortification 1 (4)

Breast milk with fortification 15 (60)

Preterm formula milk 9 (36)

Caffeine 20 (80)

Patent ductus arteriosus 0

Transfusion characteristics, median (IQR)

Pretransfusion hemoglobin, g/dL 9.3 (8.6-10.3)

Packed red blood cells hemoglobin, g/dL 19.7 (18.8-20.0)

Age of packed red cell transfusion,median (IQR), d

9 (4-23)

Necrotizing enterocolitis within 72 h of thestudy period

0

Feed intolerance within 72 h of thestudy period

0

Abbreviation: IQR, interquartile range.

SI conversion factors: To convert hemoglobin to grams per liter, multiply by 10.a Data are presented as number (percentage) of study participants unless

otherwise indicated.




during this period that would have caused significant movement artifacts. The removed segmentswere replaced with the phrase “not a number,” which is recognized by Matlab,39 version 9.3 (TheMathWorks Inc) and ignored for all subsequent processing.

The 4-hour period before the beginning of a transfusion was designated as transfusion epoch(TE) 0. The 24-hour period after the completion of transfusion was divided into 3 epochs each of 8hours’ duration (TE1: first 8 hours; TE2: 9-16 hours; and TE3: 17-24 hours) (Figure 1A). Because thefeeding timings in relation to transfusion varied in different infants, a single feeding event was chosenfor the analysis from each TE based on predefined criteria as the first feeding event during each TEthat did not overlap with care tasks. No feeding analysis was performed during the intratransfusionperiod because most feeding events extended on either side of the intratransfusion period.

Each feeding event within each epoch was divided into a preprandial feeding phase (FP0: 15minutes before the beginning of a feeding) and 4 postprandial feeding phases (FP1: 0-15 minutesafter the beginning of the feeding; FP2: 16-30 minutes after the beginning of the feeding; FP3: 31-45minutes after the beginning of the feeding; and FP4: 46-60 minutes after the beginning of thefeeding) (Figure 1B). The predefined periods were chosen to capture tissue oxygenation changes atdifferent time points after the commencement of a feeding because feeding is associated with asignificant and progressive increase in superior mesenteric artery flow that commences by 15minutes and peaks by 30 to 45 minutes after a feeding.40-42 Mean FTOEs and FTOEc were derivedfrom the real-time StO2 and SpO2 data for each infant within FPs (FP0-FP4) and TEs (TE0-TE3).

Statistical AnalysisWe analyzed FTOEs and FTOEc using a mixed model for repeated measures (MMRM) with FPs (FP0-FP4) and TEs (TE0-TE3) fitted as factors. We tested whether the association between FTOE and FPsdiffered across TEs by fitting an interaction term to the MMRM. The primary MMRM modelingapproach (with TE and FP fitted as factors) accommodated imbalance designs and included all 24infants. In an exploratory set of analyses (number of infants given in Table 2), we applied an MMRMmodel to each transfusion epoch separately (ie, 4 models per FTOE measure) and performed a seriesof paired comparisons between FP1 to FP4 vs FP0. The Dunnett method was used to adjust for themultiplicity of P values from these paired comparisons. All P values were 2-sided, and P < .05 wasconsidered statistically significant.

Figure 1. Outline of the Study Procedure and Feeding Analysis

Time (min)0 45 60 7515 30

Bolus feeds at12 mL/h

Transfusion eventsA

Feed eventsB

0 4TE0 (4 h)

FP0 (15 min) FP1 (15 min) FP2 (15 min) FP3 (15 min) FP4 (15 min)

TE1 (8 h)

Study period: simultaneous and continuous monitoring of StO2 and SpO2

Feed event: continuous and simultaneous monitoring of StO2 and SpO2

Time, h

Time, min

Decision totransfuse

Endpoint

TE2 (8 h) TE3 (8 h)8 16 24 32

PRBCT for 4 h

FP indicates feeding phase; PRBCT, packed red bloodcell transfusion; SpO2, oxygen saturation as measuredby pulse oximetry; StO2, tissue oxygen saturation; andTE, transfusion epoch.




Results

Demographic FeaturesOf 25 enrolled infants (13 [52%] female; median birth weight, 949 g [interquartile range {IQR},780-1100 g]; median gestational age, 26.9 weeks [IQR, 25.9-28.6 weeks]; median enrollment weight,1670 g [IQR, 1357-1937 g]; and median postmenstrual age, 34 weeks [32.9-35.0 weeks]), 1 infant wasexcluded because of corrupted NIRS data. Characteristics of potentially eligible, excluded, andanalyzed infants are depicted in Figure 2. The characteristics of the study cohort are presented inTable 1. Two infants (8%) had restricted umbilical artery flows on antenatal Doppler studies, and 3(12%) were small for gestational age. At enrollment, 5 infants (20%) were spontaneously breathingin room air without any respiratory support, 2 (8%) needed low-flow oxygen, 8 (32%) needed high-flow nasal cannula, and 10 (40%) received continuous positive airway pressure support. None hadPDA; 20 (80%) received caffeine, and 9 (36%) received formula milk during the study period. Themedian daily feeding intake was 160 mL/kg daily (IQR, 150-160 mL/kg daily). The medianpretransfusion hemoglobin level was 9.3 g/dL (IQR, 8.6-10.3 g/dL) (to convert to grams per liter,multiply by 10), and the age of transfused blood pack was 9 days (IQR, 4-23 days). None of theenrolled infants developed feeding intolerance or NEC within 72 hours after PRBCT.

Regional Splanchnic Tissue OxygenationTable 2, Figure 3, and eTable 2 in the Supplement summarize FTOEs over FPs and TEs (eTable 1 in theSupplement summarizes SpO2 and splanchnic and cerebral StO2). The primary MMRM analysesfound no evidence that the association between FP and FTOEs differed across TEs (eTable 3 in the

Table 2. Exploratory Analysis of FTOEs and FTOEc in Different FPs and TEsa

TE, FP

FTOEs FTOEc

No. Mean (SD), %Estimated Difference From FP0,% (95% CI) P Value No. Mean (SD), %

Estimated Difference From FP0,% (95% CI) P Value

0

0 24 12.06 (7.37) NA NA 24 26.23 (5.43) NA NA

1 24 11.68 (7.54) −0.39 (−2.32 to 1.55) .97 24 26.67 (5.57) 0.45 (−0.38 to 1.28) .48

2 24 13.01 (6.91) 0.95 (−0.99 to 2.88) .56 24 26.41 (5.62) 0.19 (−0.64 to 1.01) .95

3 24 12.92 (6.70) 0.86 (−1.07 to 2.80) .64 24 25.40 (5.84) −0.82 (−1.65 to 0.01) .052

4 24 13.59 (7.12) 1.53 (−0.40 to 3.46) .16 24 25.58 (5.11) −0.65 (−1.48 to 0.18) .17

1

0 22 10.55 (5.50) NA NA 22 20.45 (3.04) NA NA

1 22 11.73 (5.18) 1.18 (−1.45 to 3.81) .63 22 20.97 (4.14) 0.52 (−0.63 to 1.66) .62

2 22 12.57 (5.70) 2.03 (−0.60 to 4.65) .18 22 20.80 (3.74) 0.35 (−0.80 to 1.49) .86

3 22 12.80 (5.26) 2.26 (−0.37 to 4.88) .11 22 20.27 (3.31) −0.18 (−1.33 to 0.96) .98

4 22 13.21 (5.96) 2.66 (0.04 to 5.29) .046 22 20.05 (3.50) −0.40 (−1.55 to 0.74) .79

2

0 23 11.16 (5.46) NA NA 23 21.46 (6.49) NA NA

1 22 12.17 (4.24) 0.89 (−1.21 to 2.99) .67 22 21.49 (5.05) −0.36 (−1.79 to 1.08) .93

2 22 12.63 (4.54) 1.36 (−0.74 to 3.45) .31 22 21.96 (4.50) 0.11 (−1.32 to 1.55) >.99

3 22 11.87 (5.11) 0.60 (−1.50 to 2.69) .89 22 21.41 (4.93) −0.44 (−1.88 to 0.99) .86

4 22 11.98 (4.94) 0.70 (−1.39 to 2.80) .82 22 21.35 (4.63) −0.50 (−1.93 to 0.94) .80

3

0 21 12.79 (7.06) NA NA 21 23.00 (5.78) NA NA

1 21 12.55 (6.95) −0.24 (−2.72 to 2.23) >.99 21 23.46 (6.00) 0.46 (−0.37 to 1.29) .44

2 21 12.85 (7.89) 0.06 (−2.42 to 2.53) >.99 21 23.22 (5.92) 0.22 (−0.61 to 1.05) .91

3 21 12.53 (8.56) −0.27 (−2.74 to 2.21) >.99 21 22.69 (6.00) −0.31 (−1.14 to 0.52) .76

4 21 13.09 (7.19) 0.30 (−2.18 to 2.77) .99 21 22.69 (5.69) −0.31 (−1.14 to 0.52) .76

Abbreviations: FP, feeding phase; FTOEc, cerebral fractional tissue oxygen extraction;FTOEs, splanchnic fractional tissue oxygen extraction; NA, not applicable; TE,transfusion epoch.

a The Dunnett method was used to correct P values and 95% CIs for the 4 pairwise testsper TE.






Supplement gives the FTOE estimates from the primary MMRM model), and there was no evidenceof an overall association between FTOEs and FP (FP0: mean estimate, 11.64; 95% CI, 9.55-13.73; FP1:mean estimate, 12.02; 95% CI, 9.92-14.11; FP2: mean estimate, 12.77; 95% CI, 10.68-14.87; FP3: meanestimate, 12.54; 95% CI, 10.45-14.64; FP4: mean estimate, 12.98; 95% CI, 10.89-15.08; P = .16 forthe FP association). However, in the exploratory set of analyses applied to each transfusion epochseparately, a statistically significant difference was found between FP0 vs FP4 during TE1 (mean [SD]FTOEs during TE1, 10.55 [5.5] for FP0 vs 13.21 [5.96] for FP4; P = .046). No feeding-associatedchanges were found in TE2 and TE3.

Regional Cerebral Tissue OxygenationThe primary MMRM analyses of FTOEc found no evidence that the association between FP andFTOEc differed across TEs (eTable 4 in the Supplement gives the FTOEc estimates from this model),and there was no evidence of an overall association between FTOEc and FP (FP0: mean estimate,22.83; 95% CI, 20.99-24.68; FP1: mean estimate, 23.11; 95% CI, 21.26 -24.96; FP2: mean estimate,23.05; 95% CI, 21.20-24.90; FP3: mean estimate, 22.39; 95% CI, 20.54-24.24; FP4: mean estimate,22.37; 95% CI, 20.52-24.21; P = .22 for the FP association). Similarly, in the exploratory set of analysesapplied to each TE separately, no significant differences were found between FP0 vs FP1 to 4 in anyof the transfusion epochs (Table 2, Figure 3, and eTable 2 in the Supplement).

Discussion

In this study, we rigorously evaluated FTOE through concurrent monitoring of StO2 using NIRS andSpO2 using a pulse oximeter during 32 hours. Our primary analysis found limited evidence thatfeeding was associated with a reduction in efficiency of splanchnic oxygen utilization; however,further exploratory analyses of feeding-related changes during different posttransfusion epochsfound statistically significant worsening of FTOEs after feeding during the first 8 hours aftertransfusion (suggesting an increase in oxygen consumption or a decrease in oxygen delivery or both).We found no evidence of an association between feeding and FTOEc, indicating that cerebral tissueoxygenation was protected during feeding in the anemia and posttransfusion periods.

A postprandial increase in splanchnic tissue oxygenation has been demonstrated to occur28,43

because of mesenteric vasodilatation, mediated by the enteric nervous system and endothelial-derived substance P.44 Lack of increase15 or even worsening16,17 of postprandial splanchnic

Figure 2. Flow Diagram of the Study Participants

91 Infants aged <32 wk and weighing<1500 g receiving transfusion

25 Included in the analysis

24 Included in NIRS data analysis

1 Excluded from analysis of NIRS data

66 Excluded7 PRBCT initiated out of business hours8 Feed intolerance5 Continuous or hourly feeds

11 Receiving feed volume of <120 mL/kg/d8 PDA or ibuprogen in the previous 72 h4 Received PRBCT in the previous 72 h

4 Postmenstrual age ≥37 wk10 Sepsis or hemodynamic instability6 Refusal to consent

3 Lethal or complex congenital,cardiac, or GI anomalies

GI indicates gastrointestinal; NIRS near-infraredspectroscopy; PDA, patent ductus arteriosus; andPRBCT, packed red blood cell transfusion.







Figure 3. Feeding-Related Changes in Splanchnic Fractional Tissue Oxygen Extraction (FTOEs) and Cerebral FTOE During Different Transfusion Epochs (TEs)

7.5

17.5

15.0

Mea

n FT

OE,

%

12.5

10.0

0 2 3 4

Feeding Phase1

Splanchnic FTOEA

16

32

28

Mea

n FT

OE,

%

24

20

0 2 3 4

Feeding Phase1

Cerebral FTOEB

TE0 TE0

7.5

17.5

15.0

Mea

n FT

OE,

%

12.5

10.0

0 2 3 4

Feeding Phase1

16

32

28

Mea

n FT

OE,

%

24

20

0 2 3 4

Feeding Phase1

TE1 TE1

7.5

17.5

15.0

Mea

n FT

OE,

%

12.5

10.0

0 2 3 4

Feeding Phase1

16

32

28

Mea

n FT

OE,

%

24

20

0 2 3 4

Feeding Phase1

TE2 TE2

7.5

17.5

15.0

Mea

n FT

OE,

%

12.5

10.0

0 2 3 4

Feeding Phase1

16

32

28

Mea

n FT

OE,

%

24

20

0 2 3 4

Feeding Phase1

TE3 TE3

No feeding-associated changes were noted in cerebral FTOE during TE0, TE1, TE2, and TE3. A statistically significant increase was found in splanchnic FTOE between feeding phases4 and 0 during TE1 (P = .046). Dots represent mean values, and error bars represent 95% CIs.




oxygenation has been demonstrated in anemia and is proposed to be associated with impairment ofreflexes during low oxygenation states.16 Our findings demonstrating no evidence of improvementin postprandial FTOEs during anemia (TE0) are in alignment with the these findings.

In our exploratory analysis, there was evidence of an increase in postprandial FTOEs in the first8 hours after completion of transfusion (TE1), which would indicate a decrease in oxygen utilizationefficiency. Given that oxygen consumption is likely to be higher in the postprandial status because ofdigestive activity, we hypothesize that an increase in FTOEs would reflect the inability to meet thedemand owing to inadequate oxygen delivery. The exact reason for this paradoxical inadequateoxygen delivery after transfusion is unknown but could be associated with storage-related changesin red blood cells. This hypothesis is supported by adult, animal, and in vitro studies.15,21,22,45-47 Mariket al45 found that splanchnic oxygen availability is reduced in adults with sepsis after PRBCT withblood stored for more than 15 days and postulated that poorly deformable transfused red blood cellscause microcirculatory occlusion, leading to tissue ischemia. Simchon et al46 found that red bloodcell transfusion in rats resulted in preferential trapping of red blood cells with reduced deformabilityin splanchnic circulation. Nair et al21 found that red blood cell transfusion with blood stored for 7days in enterally fed preterm lambs promoted mesenteric vasoconstriction and impairedvasorelaxation by reducing mesenteric arterial endothelial nitric oxide synthase. With the use ofDoppler ultrasonography in preterm infants, PRBCT was associated with a decrease in celiac arteryflow47 and failure of postprandial increase in superior mesenteric artery flow.15 Marin et al22 foundthat after transfusions postprandial splanchnic tissue oxygen levels decreased significantly inpreterm infants fed during transfusion compared with infants not fed during transfusion.

Although red blood cells are stored under controlled conditions before transfusion, numerouschanges can occur (referred to as the storage lesion) that may result in reduced oxygen delivery.48 Invitro studies have found that storage lesion results in a lack of red blood cell–induced vasodilatationin hypoxic tissues because of the rapid decrease in red blood cell S-nitrosohemoglobin,49 impairedvasorelaxation attributable to reduced mesenteric arterial endothelial nitric oxide synthase,21 andreduced oxygen off-loading and red blood cell deformability attributable to a decrease in the2,3-diphosphoglycerate level.50 The median age of transfused red blood cells in our study was 9 days(IQR, 4-23 days). All red blood cells were leukodepleted, tested negative for cytomegalovirus, andwere stored in SAG-M additive solution (sodium chloride, 8.77 g/L; adenine, 0.169 g/L; glucose, 9g/L; and mannitol, 5.25 g/L). To our knowledge, no prospective studies have used NIRS technology toexamine the correlation between the age of red blood cells given to preterm infants and splanchnictissue oxygenation.

Our finding of worsening postprandial FTOEs during the first 8 hours after transfusion (TE1) thatsubsequently stabilized (TE2 and TE3) may be attributable to the recovery of a storage red blood celllesion resulting in improved posttransfusion oxygen delivery. Red blood cell deformability andoxygen unloading recover with time after transfusion. Heaton et al51 found that in adults receiving atransfusion, 2,3-diphosphoglycerate levels reached 50% within 7 hours and 95% by 72 hours aftertransfusion. Marik et al45 found similar results, demonstrating that posttransfusion splanchnicischemia lasted for at least 6 hours after a PRBCT in adults with sepsis. Using NIRS, Marin et al22

found that in preterm infants fed during transfusion, the initial decrease in postprandial splanchnicbed oxygen levels returned to the hyperemic response after the fifth feeding after transfusion.

The splanchnic StO2 values in our study were higher and corresponding FTOE values lowercompared with other published reports.32,43,52-54 Absolute readings of splanchnic oxygenation areknown to vary widely because of peristalsis, stool interference, different monitors, sensors, site ofplacement of sensors, weight, gestational age, and postnatal age.35,38,55-61 Given that there are nonormative values for splanchnic StO2, relative changes of tissue oxygenation trends over time aremore meaningful compared with absolute values.59

The absence of feeding-associated changes in FTOEc indicates that cerebral tissue oxygenationis protected after feedings during anemia and posttransfusion periods. The resilience of cerebral




oxygen kinetics, unlike splanchnic oxygen kinetics, underscores the role of cerebralautoregulation.17,62

Strengths and LimitationsThis study has strengths. Several studies have examined the association of feeding alone43,54 ortransfusion alone31,52,53,63 with splanchnic or cerebral tissue oxygenation. The strength of this studywas the comprehensive investigation of the association of feeding in the context of anemia andtransfusion with both splanchnic and cerebral tissue oxygenation. Unlike other researchers,22,63 wemeasured FTOE, which gives a better understanding of oxygen consumption–delivery coupling,rather than only the StO2 levels. Rigorous methods and incorporation of high-volume data points inthe analysis add to the strength. There is no consensus in the literature regarding transfusionthreshold in neonates, and NIRS studies vary in their transfusion threshold.22,52,53,63,64 Because ofthe lack of formal protocol regarding PRBCT, our approach could have been to perform a case-controlstudy with a matched control of infants with similar hemoglobin levels not receiving transfusion. Thisapproach was, however, considered not feasible or rational. Our study was designed so that eachinfant acted as their control (intraindividual comparison) before vs after PRBCT. Thus, adding anindependent control group (without PRBCT) would allow for an interindividual comparison thatwould have to be corrected for multiple confounders (eg, gestational age, hemoglobin level, sex,cardiorespiratory status, and feeding status) and require a large sample size that would be unfeasiblefor this study to be completed at a single site in a reasonable time. Moreover, published studies64,65

have found poor correlation (correlation coefficient, <0.5) between pretransfusion hemoglobinlevels and tissue oxygenation.

This study has limitations. Although a statistically significant change in postprandial FTOEs wasfound in an exploratory analysis, its biological significance remains uncertain. Only hemodynamicallystable infants were included because of concerns that hemodynamic instability may confoundsplanchnic perfusion independent of feeding. These exclusion criteria may explain why none of theinfants studied developed TANEC. The median pretransfusion hemoglobin level in our cohort was 9.3g/dL (IQR, 8.6-10.3 g/dL). The absence of gut compromise may also indicate that at the transfusionthreshold, an increase in FTOEs was perhaps not biologically significant. In addition, the small samplesize limits the generalizability of our findings. Moreover, we cannot exclude bias because of theselective enrollment of infants who received PBRCT during office hours. The study involved stable,premature infants with a median postmenstrual age of 34 weeks (IQR, 32.9-35.0 weeks), and as such,caution must be exercised in interpreting results of the study in more premature infants withcardiorespiratory instability. Because of the observational nature of the study, an association ratherthan the cause-effect relationship can be ascertained between feeding and splanchnic perfusion.

Conclusions

Our study explored a mechanistic basis underpinning the clinical reluctance to feeding preterminfants in the context of transfusion. We noted the worsening of postprandial splanchnic oxygenationin the first 8 hours after completion of PRBCT and the stability of postprandial cerebral oxygenationin infants with anemia and after PRBCT. Our results warrant further investigation and support theneed for adequately powered randomized clinical trials to evaluate the role of feeding in TANEC.

ARTICLE INFORMATIONAccepted for Publication: January 2, 2020.

Published: February 28, 2020. doi:10.1001/jamanetworkopen.2020.0149

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Balegar VKK et al. JAMA Network Open.





https://jamanetwork.com/journals/jamanetworkopen/pages/instructions-for-authors#SecOpenAccess/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.0149

Corresponding Author: Kiran Kumar Balegar V, FRACP, DM, Department of Neonatology, Sydney Medical SchoolNepean, Nepean Hospital, The University of Sydney, Derby Street, Kingwood, NSW 2747, Australia ([email protected]).

Author Affiliations: Department of Neonatology, Sydney Medical School Nepean, Nepean Hospital, TheUniversity of Sydney, Kingswood, Australia (Balegar V); School of Biomedical Engineering, The University ofSydney, Sydney, Australia (Jayawardhana, de Chazal); NHMRC Clinical Trials Centre, The University of Sydney,Camperdown, Australia (Martin); The Charles Perkins Center, The University of Sydney, Sydney, Australia (BalegarV, Jayawardhana, de Chazal, Nanan).

Author Contributions: Dr Balegar V had full access to all the data in the study and takes responsibility for theintegrity of the data and the accuracy of the data analysis.

Concept and design: Balegar V, Nanan.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Balegar V, Jayawardhana, de Chazal, Nanan.

Critical revision of the manuscript for important intellectual content: Balegar V, Martin, de Chazal, Nanan.

Statistical analysis: Jayawardhana, Martin, de Chazal.

Obtained funding: Balegar V.

Administrative, technical, or material support: Balegar V, Jayawardhana.

Supervision: de Chazal, Nanan.

Conflict of Interest Disclosures: Dr Martin reported serving as an investigator on the Withholding or ContinuingEnteral Feeds Around Blood Transfusion (WHEAT) trial. No other disclosures were reported.

Funding/Support: This study was supported by grant 12/191202 from the Australian Women and Children'sResearch Foundation to cover the expenses to purchase near-infrared spectroscopy sensors (Dr Balegar V).

Role of the Funder/Sponsor: The Australian Women and Children's Research Foundation had no role in the designand conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, orapproval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Lyn Downe, MD, Department of Neonatology, Nepean Hospital, The University ofSydney, Kingswood, New South Wales, Australia, provided valuable suggestions in editing the manuscript. She wasnot compensated for her work.

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65. van Hoften JC, Verhagen EA, Keating P, ter Horst HJ, Bos AF. Cerebral tissue oxygen saturation and extractionin preterm infants before and after blood transfusion. Arch Dis Child Fetal Neonatal Ed. 2010;95(5):F352-F358.doi:10.1136/adc.2009.163592

SUPPLEMENT.eTable 1. Splanchnic and Cerebral Oxygen Kinetics in Association With Feeding and Transfusion (N = 24)eTable 2. Splanchnic and Cerebral FTOE Estimates From Exploratory AnalysiseTable 3. Splanchnic FTOE Estimates From Primary MMRM Model (N=24)eTable 4. Cerebral FTOE Estimates From Primary MMRM Model (N=24)




https://dx.doi.org/10.1007/s00246-006-1379-z

https://dx.doi.org/10.1038/s41372-018-0075-1



https://dx.doi.org/10.1159/000445283

https://dx.doi.org/10.1161/01.STR.26.1.74


https://dx.doi.org/10.1055/s-0030-1247598

https://dx.doi.org/10.1136/adc.2009.163592

association of bolus feeding with splanchnic and cerebral ......2 and spo 2 feed event: continuous...

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