Near-infrared Spectroscopy in Cerebral Oxygenation Monitoring in Full-term Neonates During Transition: Prospective Cohort Study


 BackgroundBrain is the most important organ in resuscitation. NIRS-measured cerebral oxygenation is evolving brain monitoring tool for neonatal resuscitation.MethodWe undertook a prospective observational study for monitoring of cerebral oxygenation and peripheral preductal saturation at 1 , 5 and 10 minutes after birth to establish centile chart normative for monitoring of full term neonates during transition. Fractional tissue oxygen extraction was calculated as well. In addition to studying factors affecting cerebral oxygenation at those points in time.Results 60 healthy term neonates were enrolled to define reference ranges and centile charts of cerebral oxygenation at 1, 5, and 10 minutes after birth. The strongest correlations between cerebral oxygenation metrics and peripheral preductal saturation were at 5 minutes after birth. The most significant factor affecting NIRS-measured crSO2 in healthy full term neonates was mode of delivery. This work was registered in the cinicaltrial.gov NCT05158881.Conclusions Normal references of cerebral oxygenation metrics can be used to guide intervention during neonatal resuscitation. Caesarean section is the most significant factor affecting cerebral oxygenation during the transition of healthy full term neonates.


Introduction
Fetal to neonatal transition is a very complex physiological adaptation that occurs in human experience.
Disturbances can occur during transition with potentiality for longer term harm. (1) Clinical assessment of neonates using Apgar score has high inter-observer variability. (2) There are controversies over the effects on short and long term outcome after neonatal resuscitation using rst 10 minutes ranges of SpO as it does not provide information about oxygen tissue delivery. (3,4) The brain is a vulnerable organ during fetal to neonatal transition. Routine monitoring using SpO and the heart rate does not re ect cerebral oxygenation, perfusion or brain activity. Monitoring cerebral oxygenation may in uence interventions which can affect survival, as short-and long-term neurodevelopment outcomes. (5) Cerebral regional oxygen (crSO2) measured via NIRS represents a mixed tissue saturation value, thus enabling information on the balance of cerebral oxygen delivery and oxygen consumption. (1) Aim to establish normative in cerebral oxygenation measures, FTEO and cRSO2 using centile charts as well as studying different factors affecting those metrics.

Method
The present study was held at delivery rooms of the Alexandria University Maternity Hospital (AUMH) from December 2020 till August 2021. Sixty-nine full term neonates with gestational age (GA) ≥38 weeks, without any medical support and normal pregnancy development were enrolled in this study. Thirty patients are born through cesarean section and the other 30 are born vaginally. Nine cases were excluded during the rst 10 minutes; 4 cases needed an oxygen supply, 3 cases needed a respiratory support after resuscitating, 2 cases needed positive pressure ventilation during resuscitation. eFigure 1 Patients with perinatal asphyxia, intrauterine growth restriction, Birth complications (e.g. vacuum extraction or forceps application), Suspected or known brain and/ or cardiac malformations and those who need respiratory support or oxygen therapy in the rst 10 minutes of life were excluded from the study.
Measurements of crSO2 were recorded using NIRS (INVOSTM 5100C Cerebral/ Somatic Oximeter Monitor; Covidien) by placing a neonatal brain sensor on the left fronto-parietal area of the newborn's head. The regional oxygen saturation was stored every second, over 10 seconds, at end of 1, 5, and 10 minutes after birth.
The FTOE were calculated during the rst 10 minutes of life with the following formula: FTOE = (SpO2-crSO2)/SpO2. At the same time, SpO2were measured using pulse oximeter (Masimo or Nellcor) by applying a preductal pulse oximetry sensor to the right wrist. Venus blood gas samples were obtained from umbilical cord blood of all neonates and clinical status were assessed by Apgar score at 1, 5 and 10minutes of life. Informed parental consents were obtained for all enrolled newborns and the criteria for the ethical committee of the faculty of medicine in Alexandria University were strictly applied.
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. The Kolmogorov-Smirnov test was used to verify the normality of distribution. Qualitative data were described using number and percent. Quantitative data were described using range (minimum and maximum), mean, standard deviation, median, interquartile range (IQR) and percentiles. The centiles (10th, 25th, 50th, 75th and 90th) for the cTOI and cFTOE were calculated using the least mean square (LMS) method described by Cole and Green. For categorical variables, chi-squared and sher's exact tests were used to compare between different groups. To compare between two independent studied groups, student t-test and mann whitney test were used for both normally and abnormally distributed quantitative variables, respectively. Univariate and multivariate binary logistic regression analysis were constructed to identify independent risk factors (predictors) for low and high CrSo2 norms (below and above 50th centile values). Pearson and spearman correlations coe cients were used to correlate normally and abnormally distributed quantitative variables, respectively. Signi cance of the obtained results was judged at the 5% level.

Results
Table (1) show descriptive analysis of the studied cases according to demographic data (sex, GA, weight and mode of delivery), resuscitation needs, APGAR score, venous cord blood gases and clinical parameters (Heart rate at 10 minutes, CRT, preductal oxygen saturation at 1,5 and 10 minutes) There are signi cant positive correlations between cerebral tissue oxygenation and preductal oxygen saturation (pulse oximeter) at 1, 5, and 10 minutes with r 0.532*, r 0.73, and r 0.34, respectively, Figure 2.
Univariate and multivariate logistic regression analysis for the predictors of low normal and high normal cerebral tissue oxygenation at 1 ,5, and 10 minutes,Table3. The most signi cant factor affecting cerebral oxygenation at 5 and 10 minutes is the mode of delivery. Infants born by cesarean section have signi cantly higher SPO2 and crSO2, and signi cantly lower FTOE at 5 and 10 minutes after birth. Despite no signi cant difference in cerebral oxygenation metrics and SPO2 between infants born by Cs or vaginally in the rst 1 minute after birth, the rate of rise from 1st to 5 minutes was signi cantly higher in infants born vaginally.

Discussion
The NIRS technology is approximately 45 years old and there is an increasing interest to use NIRS in the rst few minutes after birth. NIRS-measured CrSO and preductal SpO2 monitoring can guide oxygen supply and the medical support during neonatal transition. (1) Cerebral regional oxygen saturation values can be maintained between 10th and 90th centile, thus preventing hypoxic and hyperoxic brain injury. (6) The rst prerequisite for use of NIRS as a guide for intervention needs during resuscitation is establishing normal ranges for regional oxygenation metrics in rst 10 minutes after birth.
Median crSO readings in our study are similar to those established by Gerhard Pichler et al (2013) in term neonates who did not need a respiratory support with NIRS device (INVOS 5100). Median readings obtained in their study were 41% (23-64) at 2 minutes, 68% (45-85) at 5 minutes and 79% (65-90) at 10 minutes. (7) Nastase L study (2017) used the same criteria with the same NIRS device ( INVOS 5100) and median crSO readings were 35% (15-58.2) at 1 minute, 64%(46.2-85) at 5 minutes and 76% (67.6-87.4) at 10 minutes. (8) Higher 1 minute readings of crSO in our study might be attributed to maternal exposure to 40% oxygen through face mask during cesarean section and this was not mentioned in Nastase L study.
Ranges of crSO may vary according to several factors such as the NIRS device used, gestational age, and need for respiratory support. Cerebral oxygenation measures vary according to the used NIRS devices as the calculated values are determined by different algorithms used by competing vendors. (6) Brain oxygenation metrics are higher among the preterm infants and this is mostly due to impaired cerebral autoregulation in preterm neonates and the different ability of brain tissue to extract oxygen as explained by Lucia Gabriella (2009). (9) Also neonates who need respiratory support have a compromised cerebral tissue oxygenation compared to those without disturbed transition. This difference indicates that decreased crSO in neonates with respiratory support maybe due to decreased arterial oxygen saturation levels and compromised perfusion as found by Schwaberger B (2014). (10) Those factors won't affect readings in the current work as we included only healthy, full term neonates monitored with the same device. In order to discover other factors that might affect cerebral oxygenation in healthy full term neonates we used 50th centile values to divide patients into high and low norms. Then we constructed logestic regression models to discover the signi cant predictors of low and high norms. The only signi cant factor was the mode of delivery at 5 and 10 minutes. Therefore, we divided the patients into Csection and NVD groups and compared them as regard different clinical and oxygenation parameters.
Preductal Oxygen saturation (SpO ) measures were compared at 1, 5 and 10 minutes of life in patient delivered vaginally or by cesarean section table 5. Oxygen saturation at the rst minute showed no statically signi cant difference between the 2 studied groups (p=0.146). This might be attributed to maternal oxygen administration through face mask with FIO [fractional extraction of oxygen) 40% which reported in all cases during cesarean delivery. While, the difference in SpO at 5 and 10 minutes were statically signi cant between the normal vaginal and the cesarean groups (p=0.001, p=0.031 respectively). This is might be secondary to the delayed clearance of fetal lung uid during cesarean delivery. (11) Regional cerebral oxygenation (crSO ) was recorded during the rst 10 minutes of life simultaneously with peripheral arterial oxygen saturation through pulse oximeter. Table ( (13,14) The rate of rise from 1 to 5 minutes of life was statically signi cantly higher among the vaginal group (36%) than the cesarean group (22%) with p<0.001.
FTOE indicates an increase of oxygen consumption due to increased cerebral metabolic rate, decreased oxygen delivery or both. (15) Fractional tissue oxygen extraction at 1, 5 and 10 minutes were calculated and compared between the patients delivered vaginally or by cesarean section. Despite crSO was not different in the 2 groups, FTOE at 1 minute showed a near signi cant difference between the 2 groups with median value (0.38) in the cesarean group and (0.52) in the normal vaginal group(p=0.07 in patient delivered vaginally or by cesarean section, respectively. FTOE considerably decreased at 5 and 10 minutes and showed statically signi cant difference between the 2 groups (p=0.005, p=0.004 respectively), in agreement with Nastase L study (2017). (8) Better cerebral oxygenation metrics and preductal peripheral oxygen saturation were found in vaginal than cesarean group that might be attributed to higher cerebral blood ow due to higher level of carbon dioxide which is the most potent cerebral vasodilator. It is logic that there must be correlation between SPO2 and cerebral oxygenation parameters (crSO2 and FTEO). However, their relationship is not constant at 1, 5 and 10minutes. The most signi cant correlations were at 5minutes SPO2 and cerebra oxygenation parameters (crSO2 and FTEO) with r=0.6 and r=0.4, respectively.
The discrepancy in the strength of correlation could be explained by the following factors: rst; crSO reaches the plateau earlier than the peripheral arterial saturation (SpO ) and the preferential oxygen delivery to the brain during the rst few minutes after birth. (15) Second; the cerebral vascular bed constricts after 5 minutes in response to the postnatal rise in the blood oxygen content to protect the brain from excessive oxygen exposure.third; Kehrer M et al (2005) suggested by that the increasing left-toright shunt through the patent ductus arteriosus together with an inadequate compensatory increase in left ventricular output might decrease the cerebral blood ow . (17) The limitations of this work is the small sample size the major point of strength that it is the only known published data and centiles abut NIRS monitoring in neonatal transition from developing countries. Conclusions NIRS-measured crSO2 guided by centile charts become the most promising method which provides feasible rapid continuous non-invasive monitoring and quanti cation of cerebral oxygenation during resuscitation. It might in uence interventions needs during resuscitation and might be a predictor for short-and long-term outcome. The most signi cant factor affecting NIRS-measured crSO2 in healthy full term neonates is the mode of delivery.

Declarations Consent for publication
Informed consent was obtained from parents or authorized legal representatives of all newborns who participated in the study for publication of anonymous patients' data.

Availability of data and material (data transparency)
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request

Ethics-approval and consent to participate
The study protocol has been approved by the Research Ethics Committee of Alexandria faculty of medicine. Approval no. is 0106540 in 17-9-2020 (date of approval). IRB no. is 00012098 and FWA no. is 00018699. Written informed consent was obtained from parents or authorized legal representatives of all newborns who participated in the study for publication of anonymous patients' data.

Competing interests Statement
The authors have no con icts of interest to declare.

Funding Sources
This research did not receive any speci c grant from funding agencies in the public, commercial, or notfor-pro t sectors.

Acknowledgement
We are grateful and thankful all the patients, parents and staff of the NICU of Alexandria university that participated in the study.

Authors' contributions
Hesham Abd EL-Rahim Ghazal conceived of the presented idea.  Mean ± SD.   Centile charts for cRsO2 and FTEO at 1, 5 and 10 minutes after birth in healthy full term neonates.