Maintaining optimal cerebral blood flow during transition is crucial for extremely low gestational age neonates (ELGANs), due to a high risk of brain injury during this period. Historically, clinicians in neonatal intensive care units (NICUs) have relied on arterial blood pressure (BP) as a surrogate marker of end-organ perfusion, including cerebral perfusion. BP has been shown to correlate poorly with left ventricular output (LVO) measured on echocardiography (1). Further, therapies targeted at maintaining arbitrary BP values have not proven to reduce brain injury (2). As BP alone is an unreliable measure of hemodynamic stability and provides limited diagnostic insight on the etiology or the impact on tissue perfusion, there has been a move towards using newer modalities such as targeted neonatal echocardiography (TNE) and prefrontal cerebral near-infrared spectroscopy (NIRS) to provide a comprehensive hemodynamic evaluation (3). From a clinical perspective, an integrative approach by combining information obtained from multiple modalities is likely to provide a more holistic appraisal of cardiovascular and brain health. Increasingly, over the last decade, TNE is being used in many NICUs across the world for the assessment of cardiac function and outputs; however, its widespread use is limited by a lack of round-the-clock availability of personnel trained in imaging and interpretation. Although cerebral NIRS is now being adopted by a handful of NICUs for continuous real-time monitoring of cerebral oxygenation and perfusion, it is not yet the standard of care for cerebral monitoring in preterm infants during periods of vulnerability such as during postnatal transition. The standard of care in most centers is to rely on arbitrary, and unproven, measures of BP (4). Even in centers with hemodynamic programs providing advanced echocardiography measures and enhanced diagnostic precision, there may be no longitudinal neurophysiologic surveillance which is a gap in practice given the vulnerability of the immature brain. While the practical application of multi-modal monitoring in NICUs is still evolving, the knowledge of how cerebral blood flow is affected by changes in systemic hemodynamics is important but remains poorly investigated. Whether BP or echocardiographic markers of systemic blood flow correlate with cerebral oxygenation is not clearly understood with conflicting findings in the literature (5–11). Therefore, the primary aim of this study was to describe the relationship of cerebral oxygenation with cardiac output, BP, and cerebral Doppler measurements in ELGANs during the first 72 h after birth. We hypothesized that an increase in cerebral oxygenation during the transitional period is linearly correlated with cardiac output and superior vena cava (SVC) flow but not with BP.

Fifty ELGANs with a median (range) gestational age (GA) of 25.9 (23.1–27.9) weeks and birthweight of 795 (660–875) grams were recruited (Table 1). Two infants received chest compressions at birth, none received epinephrine. Of these, one infant was classified as ‘clinically stable’ and the other as’ clinically unstable’ because of aPH. Thirty-nine infants (78%) had a clinically stable course in the first week and the remaining 11 patients were classified as unstable; specific co-existing pathologies were as follows: IVH Grade III/IV (n = 4, of which one infant died due to Grade IV IVH and one developed SIP); aPH (n = 4); SIP (n = 2, of which one infant with IVH Grade III); mortality due to septic shock related to late onset sepsis on day 4 of life (n = 1). None of the infants had culture-positive early-onset sepsis.

Our data suggests that during postnatal transition in ELGANs, despite major changes in pulmonary and systemic blood flow, there was no relationship detected between cerebral oxygenation and either echocardiography measures of systemic blood flow or BP for the range of measured values.

Previous literature on this subject is conflicting. In an earlier report, Kissack et al. reported that there was a negative correlation between CFTOE, measured after partial jugular venous obstruction, and LVO; however, this relationship was observed only in the presence of hypocarbia and when LVO was below the 5th percentile (5). Moran et al. reported a positive correlation between CrSO₂ and SVC flow on postnatal day 1 in infants with birthweight <1,500 g (n = 27, r = 0.53) (7). Janaillac et al. reported that CrSO₂ correlated with SVC flow in low cardiac output states during the first 72 h (n = 13, r = 0.74 at 6 h and r = 0.86 at 24 h) (9). Sortica Da Costa demonstrated that RVO and LVO correlated with CrSO₂ at 24 h in infants with IVH (n = 13, r = 0.75) (10). On the other hand, several studies reported no correlation between either CFTOE (6) and CrSO₂ (7) and RVO or LVO, or between CrSO₂ and left ventricular ejection fraction (LVEF), Tricuspid annular plane systolic excursion (TAPSE) or SVC flow during transition (8, 11). Our findings are consistent with the latter observations (6–8, 11). The inconsistency between studies may relate to variance in patient demographics, illness severity, or developmental factors; however, a more plausible explanation is the fact that the interactions between systemic blood flow, arterial pressure and gestation-dependent changes are sufficiently complex and variable that binary correlative analyses may be overly simplistic. Unmeasured confounders include gestation-dependent vascular reactivity, and vascular compliance which may be influenced by arterial remodeling, and cellular metabolism.

Unlike other studies, we investigated the relationship between cerebral oxygenation and the components (systolic, and diastolic) of BP separately, rather than MBP alone. Pfurtscheller et al. studied the correlation between CrSO₂ and MBP, DBP and SBP separately obtained by oscillometry in the first 15 min after birth in preterm neonates (16); however to our knowledge, such correlation over the 72 h after birth has not been reported before. Although most clinicians use MBP as an overall marker of cardiovascular health, with MBP < GA in mm Hg arbitrarily used as a definition of hypotension, it is now increasingly being recognized that this is a physiologic simplification. Studies of hypotension treatment show no apparent benefit when these thresholds are used (2). Biologically, SBP and DBP are considered to reflect stroke output and systemic vascular resistance, respectively. Therefore, some commentators have suggested treatment selection based on these subcomponents, although evidence of efficacy is limited (17, 18). In our cohort, we did not see any meaningful relationship between CrSO₂ or CFTOE and SBP/DBP/MBP. A plausible explanation for the lack of relationship between cerebral oxygenation, and cardiac output and BP may be the presence of intact cerebral autoregulation. The finding of positive correlations between CrSO₂ and SBP/MBP at a single time-point (17.3 h) is likely a chance finding. Alternatively, it may reflect fluctuations of cerebral autoregulation with periods of intact and impaired autoregulation (16). We also studied the correlation of cerebral oxygenation with MCA.MV as a more direct measure of cerebral blood flow, which, to our knowledge has not been studied before. However, we did not demonstrate a significant relationship with CrSO₂ or CFTOE, which possibly reflects the role of cerebral microvasculature in autoregulation. It is also possible that the relationship between BP, cardiac output and cerebral blood flow is non-linear, multidirectional, and variable such that simple correlative analyses may not yield a meaningful pattern.

There are additional confounders that may impact the relationship between BP or cardiac output, and cerebral oxygenation. For example, during postnatal transition, significant left to right shunts across the PDA and PFO may increase pre-ductal LVO and RVO, respectively, further confounding the relationship between LVO and CrSO₂. Even after excluding infants with a PDA measuring >1.5 mm and PFO > 2.0 mm, no correlation between LVO and RVO with CrSO₂ and CFTOE at any time-point was noted. The lack of any relationship with measures of systemic blood flow may relate to the low number of patients with critically low cardiac output in this study.

The pattern of change over time in cerebral oxygenation and hemodynamic parameters presented in Table 2 is consistent with published literature (19–21). The increase in LVO and RVO is likely related to the change in loading conditions and myocardial adaptation over time (19). The change in cardiac output also is likely responsible for an increase in SBP seen in our cohort, but not DBP or MBP (20). Although the increase in CrSO₂ was statistically significant, pairwise comparisons did not show any significant change compared to the baseline value. CFTOE, MCA.MV and SVC flow may likely be related to preserved cerebral autoregulation as SVC flow is representative of upper body and cerebral flow (21, 22).

Our data highlights the limitations of readily available hemodynamic indices that govern end-organ perfusion, to estimate cerebral blood flow. This is especially important in clinical decision making such as the management of transitional hypotension based on numerical values of BP. Although previous studies have shown a correlation between LVO and/or SVC flow and deranged cerebral neurophysiology in subgroups of neonates in individual studies (5, 9), we did not observe such a relationship. Therefore, longitudinal evaluation of cerebral oxygenation, together with other clinical markers or tissue perfusion, may guide clinical management in patients with a low cardiac output state.

We acknowledge the following important limitation; specifically, due to the small sample size and low number of infants who were clinically unstable hypotensive or had low LVO or SVC flow, correlation between cerebral and systemic hemodynamics in this high-risk population was not performed. Moreover, the levels of hemoglobin and carbon dioxide and administration of medications can also influence CrSO₂. However, we were unable to account for them as the timing of bloodwork did not align with the specific neurophysiologic measurements. Further, prophylactic indomethacin may cause cerebral vasoconstriction and may potentially affect cerebral blood flow by modulating PDA shunt, which we were unable to account for (23). Further, in our study, we used time-point values to study correlation, which is one of the other limitations of our research. Time correlation measurements between mean blood pressure and CrSO₂, are preferred for studying cerebral autoregulation (24). Therefore, objective measures of cerebral autoregulation are likely to be informative, especially in the critical management of sick and unstable neonates. Although the measurement of cerebral autoregulation in preterm infants is an emerging area of research (25), there is ongoing debate as to the most accurate algorithms and methods (24). The absence of bedside measures that estimate cerebral blood flow highlights an urgent need for robust studies aimed toward the translation of real-time continuous autoregulation measurement at the bedside as a part of clinical practice, especially for the sickest and most vulnerable preterm infants. Future research on this subject should focus on the most unstable neonates; in particular, an adequately powered study in infants with very low cardiac output, extreme hypotension or shock would the enable characterization of the relationship in the highest-risk patients while allowing to adjust for confounders would be of most value.