Impact of Carbon Dioxide on Cerebral Oxygenation and Vital Parameters in Stable Preterm and Term Infants Immediately after Birth

Carbon dioxide (pCO₂) is one of the most potent mediators of cerebral autoregulation inducing changes in cerebral vessels’ tone and influencing cerebral blood flow (CBF) [1, 2]. Cerebral autoregulation enables constant CBF, independent of changes in cerebral perfusion pressure as long as the blood pressure range is within the autoregulatory plateau [3]. Above the autoregulatory plateau, CBF increases and below, CBF decreases in a pressure-passive manner [4]. An impaired autoregulation leads to linear changes of CBF depending on changes in blood pressure [5]. An increase in pCO₂ attenuates CBF autoregulation. Higher pCO₂ is associated with cerebral vasodilatation and an increase in CBF, while a reduction in pCO₂ leads to cerebral vasoconstriction and a decrease in CBF [6, 7]. Significant fluctuations in pCO₂ have already been described to be associated with neurodevelopmental morbidities, whereby fluctuations and extreme high or low values within the first few days after birth are associated with a higher risk of cerebral impairment [8, 9].

Cerebral regional tissue oxygen saturation (crSO₂) can be monitored by continuous noninvasive measurements of oxygenated (HbO₂) and deoxygenated hemoglobin (Hb) using near-infrared spectroscopy (NIRS) [10, 11]. Near-infrared light propagates through tissue, and certain wavelengths are differently absorbed by HbO₂ and Hb [12]. Cerebral fractional tissue oxygen extraction (cFTOE) and cerebral tissue oxygen extraction (cTOE) can be calculated out of crSO₂ and arterial oxygen saturation (SpO₂).

Monitoring of cerebral oxygenation with NIRS in the delivery room during the immediate fetal-to-neonatal transition period is well established [13, 14]. Low cerebral oxygenation during immediate transition is associated with cerebral injury [15], whereby cerebral oxygenation can be improved by using NIRS monitoring and dedicated interventions [16]. However, knowledge of influencing parameters on cerebral oxygenation during immediate uncomplicated transition is still limited. Metabolic parameters like blood glucose [17] and circulatory parameters like ductus arteriosus and persistent foramen ovale have been demonstrated to influence cerebral oxygenation [18, 19]. However, so far, there are no investigations on the potential influence of pCO₂ on crSO₂, cFTOE, and cTOE in stable infants during the immediate transition after birth – within the first 15 min after life.

The aim of the present study was therefore to evaluate the potential correlation between pCO₂ and crSO₂, cFTOE, and cTOE (measured with NIRS), with routine monitoring parameters (SpO₂, heart rate [HR], mean arterial blood pressure [MABP], and rectal body temperature), with partial pressure of oxygen (pO₂), and with blood glucose in preterm and term infants without medical support 15 min after birth. We hypothesized that higher pCO₂ values would be associated with higher crSO₂ and lower cFTOE and cTOE values 15 min after birth due to increased CBF as a result of vasodilatation, with a weaker effect in preterm infants due to their more immature autoregulation.

In the present study, a post hoc analysis of secondary outcome parameters of prospective observational studies, conducted at the Division of Neonatology, Department of Paediatrics and Adolescent Medicine, Medical University of Graz, Austria, between July 2009 and September 2018, was performed. The studies were approved by the Regional Committee on Biomedical Research Ethics (EC Nos. 19-291 ex 07/08, 23-403 ex 10/11, and 27-465 ex 14/15). Written parental informed consent was obtained before birth and inclusion in each study.

Preterm and term infants delivered by caesarean section, who received cerebral NIRS monitoring during the first 15 min after birth as participants of one of the prospective observational studies, were included. Furthermore, for inclusion into the present post hoc analysis, a heel-stick blood sample for blood gas and hemoglobin analysis was required. This had to be performed within 14–18 min after birth at the discretion of the respective attending neonatologist, to correlate the results with the NIRS and routine monitoring parameters at minute 15 after birth. Exclusion criteria were major congenital malformations and the need for supplemental oxygen and/or (non-)invasive respiratory support.

Antepartum medical histories were collected, and demographic data including gestational age, birth weight, sex, umbilical artery pH, Apgar scores, Hb concentration, and fetal hemoglobin (HbF) concentration were documented. Cord clamping was routinely delayed for 30 s after birth. Infants were dried and placed in the supine position under an overhead heater. The NIRS sensor was fixed on the left frontoparietal head using a modified CPAP cap or an elastic gauze bandage immediately after birth. NIRS measurements (crSO₂) were performed with the INVOS 5100C Cerebral/Somatic Oximeter Monitor (Medtronic, Minneapolis, MN, USA) with a neonatal transducer. Pulse oximetry was applied on the infants’ right hand or wrist. SpO₂ and HR were measured with the IntelliVue MP30 monitor (Koninklijke Philips, The Netherlands). The monitoring was performed continuously during the first 15 min after birth. cFTOE and cTOE were calculated out of SpO₂ and crSO₂ by the following formulas: cFTOE = (SpO₂ − crSO₂)/SpO₂ and cTOE = SpO₂ − crSO₂ [20].

For noninvasive blood pressure measurements (IntelliVue MP50 monitor; Koninklijke Philips, The Netherlands) at minute 15 after birth, the pneumatic cuff was placed on the infants’ right upper arm. Rectal body temperature was routinely measured once in minute 15 after birth.

All variables were stored in the multichannel system alpha trace digital MM (BESTMedical Systems, Vienna, Austria) for subsequent analysis. For the present study, mean values of crSO₂, SpO₂, and HR obtained during a 60-s period at minute 15 after birth were analyzed. Values of SpO₂ and HR were stored every second, whereby the sampling rate for crSO₂ was 8 s. As a quality criterion, values of crSO₂ and SpO₂ were eliminated when crSO₂ was higher than SpO₂.

pCO₂, pO₂, Hb, HbF, glucose values, and pH were obtained from capillary blood (ABL 800 Flex; Fa. Drott, Wiener Neustadt, Austria) according to the local standard operating procedures.

Demographic, NIRS, and routine monitoring data are presented as n (%), mean and standard deviation, or median and interquartile range, as appropriate. Comparisons of categorical baseline characteristics (pCO₂, demographic and monitoring data, and results of blood analyses) between preterm and term infants were performed using the χ² test and for continuous variables using the t test or Mann-Whitney U test, as appropriate. Correlation analyses between pCO₂ and NIRS parameters (crSO₂, cFTOE, and cTOE), clinical routine monitoring parameters (SpO₂, HR, MABP, and rectal temperature), pO₂, and blood glucose were calculated separately for preterm and term infants using Pearson correlation for normally distributed data and the Spearman’s rank correlation for not normally distributed data.

A p value <0.05 was considered statistically significant. These values were considered in an explorative sense; therefore, no multiple testing corrections were performed. Statistical analyses were performed using SPSS Statistics 24 (IBM, Armonk, NY, USA).

A total of 148 preterm and 511 term infants, who were included in the prospective observational studies, were eligible. Eleven preterm and 84 term infants were finally included in the present observational study (shown in Fig. 1). Demographic data, NIRS and routine monitoring parameters, and results of the blood gas analysis of the included preterm and term infants are summarized in Table 1. Correlation analyses are presented in Table 2.

Capillary blood gas samples were taken at a median (interquartile range) of 16.5 (15.5–17.2) and 16.0 (15.9–16.5) minutes after birth in preterm and term infants, respectively. No differences were observed between preterm and term infants in NIRS parameters, pCO₂, pO₂ Hb, blood glucose, and pH. HbF was significantly higher in preterm compared to term infants (shown in Table 1). In routine monitoring, no statistically significant differences between preterm and term infants were observed except for rectal body temperature.

In preterm infants, pCO₂ correlated significantly negatively with crSO₂ and positively with cFTOE and cTOE. Furthermore, in other parameters, no correlation with pCO₂ was observed (shown in Fig. 2a–d; Table 2).

In term infants, pCO₂ did not correlate with crSO₂, cFTOE, cTOE, SpO₂, HR, MABP, rectal temperature, or blood glucose. However, pCO₂ correlated significantly negatively with pO₂, nevertheless with only a weak correlation (shown in Fig. 2e–h; Table 2).

To our knowledge, this study is the first that analyzed potential correlations between pCO₂ and cerebral oxygenation during the immediate fetal-to-neonatal transition period in stable preterm and term infants. We showed that in preterm infants, pCO₂ values correlated negatively with crSO₂ and positively with cFTOE and cTOE, whereas no such correlation was observed in term infants. Furthermore, in preterm infants, a trend to positive correlation of pCO₂ with HR and MABP was observed. In term infants, there was no correlation between pCO₂ and routine monitoring parameters.

Previous studies reported pCO₂ values of 49–76 mm Hg at birth, with a decrease to 46–57 mm Hg within the first 10 min after birth [21]. In our study, pCO₂ values at 15 min after birth were within these ranges.

Correlations between pCO₂ and cerebral oxygenation were more pronounced in preterm infants compared to term infants. However, the direction of the correlation in preterm infants was not as we expected, as contrary to our hypothesis, higher pCO₂ values were associated with lower crSO₂ and higher cFTOE and cTOE values in preterm and term infants 15 min after birth. There are several hypotheses to explain these findings.

First, in the present study, preterm infants with higher pCO₂ values showed a trend to lower SpO₂ and pO₂ values in minute 15 after birth. SpO₂ and pO₂ influence crSO₂, cFTOE, and cTOE because oxygen delivery to the brain depends on SpO₂ and pO₂. Thus, lower SpO₂ and pO₂ values are associated with lower crSO₂ and higher cFTOE and cTOE values. The association of lower pO₂ with higher pCO₂ might be explained by a prolonged pulmonary transition due to reduced aeration of the lungs even in clinically stable infants showing lower SpO₂ values, though within normal ranges.

Second, immediately after birth, both pCO₂ and pO₂ are potent mediators for changes in cerebral vascular resistance. The strong vasodilatory influence of high pCO₂ values is a well-known phenomenon. In spontaneously breathing preterm infants 2 and 3 h after birth, the pCO₂-CBF reactivity has already been demonstrated by Pryds et al. [22], whereby CBF is well regulated within normal ranges of pCO₂ values. A similar effect of pCO₂ on CBF was observed in preterm infants in need for mechanical respiratory support within the first 3 days after birth [7]. Changes of CBF are described to be between 10% and 30% per kPa of pCO₂ in very preterm infants after immediate transition [23]. However, besides pCO₂, pO₂ is one of the most potent mediators inducing changes in the tone of the cerebral vessel and influences cerebral autoregulation and CBF. Below a pO₂ threshold of approximately 50 mm Hg, an increase in pO₂ has a strong vasoconstrictive effect on cerebral vessels [24]. pO₂ levels usually increase from 15–20 mm Hg to 46–57 mm Hg within the first 10 min after birth [25]. The vasoconstrictive effect of the pO₂ increases during immediate transition, up to minute 15 after birth, potentially may have outweighed the vasodilatative effect of higher pCO₂ values [6]. A decrease in pCO₂ values is further associated with a decrease in CBV in preterm and term infants within the first minutes after birth [24]. In summary, the present findings suggest that in preterm infants, the vasodilatative effect due to hypercarbia does not outweigh the vasoconstrictive effects of the increasing pO₂ values after birth.

In addition, in both preterm and term infants, higher pCO₂ levels were associated with lower pO₂ levels reaching significant negative correlation only in term infants. These associations suggest lower crSO₂ levels with higher pCO₂ due to the lower pO₂ as observed in preterm infants. In term infants, however, higher pCO₂ associated with lower pO₂ was not associated with crSO₂ suggesting that the vasodilatative effect of pCO₂ increased CBF to maintain oxygen delivery to the brain.

Third, in the present study, preterm infants had higher HbF levels compared to term infants. Higher HbF concentrations lead to a left shift of the oxygen dissociation curve (ODC), causing an increased affinity for oxygen (O₂) [26] that might also explain the different findings in the 2 groups [27]. At birth, there is a predominance of HbF, with a higher total amount in preterm infants compared to term infants. However, HbF is associated with reduced unloading of oxygen to tissue [28]. In the present study, the higher HbF in preterm infants results in ODC shift to the left causing a higher affinity of hemoglobin to oxygen, which may have partially antagonized the right shift of the ODC because of the higher pCO₂. This may especially explain the increase of cFTOE and cTOE with increasing pCO₂ values. Besides HbF, the metabolic parameter blood glucose has already been described to correlate negatively with crSO₂ [18]. In the present study, however, there was neither a difference in blood glucose levels between preterm and term infants nor a correlation between pCO₂ and blood glucose that might have confounded the present findings.

Fourth, cerebral oxygenation is dependent on oxygen delivery to the brain which is influenced by cardiac output and blood flow in the large arteries. The cardiac output and blood flow in large arteries is influenced by stroke volume, HR, and shunts. HR showed a nonsignificant positive correlation with pCO₂ in preterm infants that would suggest a higher cardiac output. However, since no echocardiography was performed, without information on stroke volume/myocardial function and especially on intra- and extracardial shunts, we cannot rule out cardiac output clearly. During the immediate postnatal transition period, the closure of the ductus arteriosus and foramen ovale leads to changes in the direction of the blood flow. In term infants, the closure of the ductus arteriosus starts immediately after birth, but it is completely closed in most term infants within 48–72 h after birth [29]. The influence of an open ductus arteriosus and foramen ovale on cerebral oxygenation plays an important role during postnatal transition [18]. Baik et al. [19] observed that the sum of ductus arteriosus and foramen ovale diameter correlated negatively with cerebral oxygen saturation due to higher left-to-right shunt volume in term infants. Furthermore, higher shunt volumes due to the ductus arteriosus and foramen ovale lead to more pronounced left-to-right steal phenomena. A comparable finding has been described by Fuchs et al. [30] in very-low-birth-weight infants, reporting that oxygen delivery to the brain depends on cardiac output. Lemmers et al. [31] described a reduction of crSO₂ in preterm infants born before 32 weeks of gestation in association with a hemodynamically significant ductus arteriosus. The ductus arteriosus in preterm infants is thin walled and less muscular compared to those in term born infants, rendering a complete closure immediately after birth less likely [29]. Ductus arteriosus closure is less pronounced in preterm infants compared to term infants during immediate transition especially in case of hypercarbia due to its vasodilatative effect on the ductus arteriosus [32]. This hypothesis is further supported by the fact that the difference between systolic and diastolic blood pressure was more pronounced in preterm infants compared to the term infants in the present study. Therefore, in preterm infants, higher pCO₂ values may be associated with a higher steal phenomenon compared to term, causing a decrease in CBF and oxygen delivery to the brain, ultimately leading to lower crSO₂ and higher cFTOE and cTOE.

There were limitations in the present study. First, analyzed preterm and term infants showed pCO₂ values within acceptable ranges for the immediate transition period. pCO₂ values outside normal ranges, which are associated with an impaired autoregulation and changes in CBF, might influence cerebral oxygenation, cFTOE, and cTOE more than it was observed in this present study. Second, no measures of CBF and cerebral blood volume were performed, as this study analyzed secondary outcome parameters of observational studies. Direct measures of CBF might have allowed us to understand autoregulation better. Third, we can only assume a possible left-to-right shunt via the ductus arteriosus and foramen ovale especially in preterm infants, as no echocardiography was performed. Fourth, the number of analyzed preterm infants in this present study is quite low and included mainly moderate to late preterm infants, due to the inclusion criterion of no need for respiratory or medical support and the short time period between 14 and 18 min after birth for performing blood gas analysis.

To conclude, we found a significant negative correlation between pCO₂ and crSO₂ and a significant positive correlation between pCO₂ and cFTOE and cTOE after immediate postnatal transition in preterm infants. There were no associations observed in term infants at all, except for pCO₂ and pO₂. The present findings suggest that the vasodilatative effect of high pCO₂ levels that would normally result in an increase of cerebral perfusion and oxygen delivery and an increase of crSO₂ levels is less pronounced in preterm infants during immediate transition. This vasodilatative effect of pCO₂ is even outweighed by other influencing parameters causing a decrease in crSO₂. This might be even more important in compromised extremely preterm infants, especially if pCO₂ values are above or below normal ranges.

We thank the parents for their trust, so we were allowed to investigate their infants. We also thank all the staff members, especially Evelyn Ziehenberger, for contributing to this study.

The studies analyzed in this post hoc analysis were approved by the Institutional Ethical Review Board of the Medical University of Graz, EC Nos. 19-291 ex 07/08, 23-403 ex 10/11, and 27-465 ex 14/15. Written parental informed consent was obtained before birth and inclusion in each study.

The authors have no conflicts of interest to declare.

No funding was received.

C.W. and G.P. conceived the research idea and finalized the methods. C.W. and G.P. analyzed the data, and C.W. wrote the first draft. C.W., M.B., B.S., L.M., B.U., and G.P. contributed to data collection, interpretation of the results, drafting, and finalizing the manuscript.

The data presented in this study are available on request from the corresponding author.