Cerebral oxygenation immediately after birth and long-term outcome in preterm neonates-a retrospective analysis.

BACKGROUND: Prematurity is associated with increased risk for morbidity and mortality. Aim of this study was to evaluate whether cerebral oxygenation during fetal-to-neonatal transition period was associated with long-term outcome in very preterm neonates. METHODS: Preterm neonates ≤ 32 weeks of gestation and/or ≤ 1500 g with measurements of cerebral regional oxygen saturation (crSO2) and cerebral fractional tissue oxygen extraction (cFTOE) within the first 15 min after birth were analysed retrospectively. Arterial oxygen saturation (SpO2) and heart rate (HR) were measured with pulse oximetry. Long-term outcome was assessed at two years using "Bayley Scales of Infant Development" (BSID-II/III). Included preterm neonates were stratified into two groups: adverse outcome group (BSID-III ≤ 70 or testing not possible due to severe cognitive impairment or mortality) or favorable outcome group (BSID-III > 70). As the association between gestational age and long-term outcome is well known, correction for gestational age might disguise the potential association between crSO2 and neurodevelopmental impairment. Therefore, due to an explorative approach the two groups were compared without correction for gestational age. RESULTS: Forty-two preterm neonates were included: adverse outcome group n = 13; favorable outcome group n = 29. Median(IQR) gestational age and birth weight were 24.8 weeks (24.2-29.8) and 760 g (670-1054) in adverse outcome group and 30.6 weeks (28.1-32.0) (p = 0.009*) and 1250 g (972-1390) (p = 0.001*) in the favorable outcome group, respectively. crSO2 was lower (significant in 10 out of 14 min) and cFTOE higher in adverse outcome group. There were no difference in SpO2, HR and fraction of inspired oxygen (FiO2), except for FiO2 in minute 11, with higher FiO2 in the adverse outcome group. CONCLUSION: Preterm neonates with adverse outcome had beside lower gestational age also a lower crSO2 during immediate fetal-to-neonatal transition when compared to preterm neonates with age appropriate outcome. Lower gestational age in the adverse outcome group would suggest beside lower crSO2 also lower SpO2 and HR in this group, which were however similar in both groups.

The Respiratory Management of the Extreme Preterm in the Delivery Room.

The fetal-to-neonatal transition poses an extraordinary challenge for extremely low birth weight (ELBW) infants, and postnatal stabilization in the delivery room (DR) remains challenging. The initiation of air respiration and the establishment of a functional residual capacity are essential and often require ventilatory support and oxygen supplementation. In recent years, there has been a tendency towards the soft-landing strategy and, subsequently, non-invasive positive pressure ventilation has been generally recommended by international guidelines as the first option for stabilizing ELBW in the delivery room. On the other hand, supplementation with oxygen is another cornerstone of the postnatal stabilization of ELBW infants. To date, the conundrum concerning the optimal initial inspired fraction of oxygen, target saturations in the first golden minutes, and oxygen titration to achieve desired stability saturation and heart rate values has not yet been solved. Moreover, the retardation of cord clamping together with the initiation of ventilation with the patent cord (physiologic-based cord clamping) have added additional complexity to this puzzle. In the present review, we critically address these relevant topics related to fetal-to-neonatal transitional respiratory physiology, ventilatory stabilization, and oxygenation of ELBW infants in the delivery room based on current evidence and the most recent guidelines for newborn stabilization.

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation.

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell's membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options.

Corrigendum: Echocardiographic Evaluation of Transitional Circulation for the Neonatologists.

[This corrects the article DOI: 10.3389/fped.2018.00140.].

Oxygen Supplementation During Preterm Stabilization and the Relevance of the First 5 min After Birth.

Fetal to neonatal transition entails cardiorespiratory, hemodynamic, and metabolic changes coinciding with the switch from placental to airborne respiration with partial pressures of oxygen of 4-5 kPa in utero raising to 8-9 kPa ex utero in few minutes. Preterm infants have immature lung and antioxidant defense system. Very preterm infants (<32 weeks' gestation) frequently require positive pressure ventilation and oxygen to establish lung aeration, a functional residual capacity, and overcome a tendency toward hypoxemia and bradycardia in the first minutes after birth. Recent studies have shown that prolonged bradycardia (heart rate <100 beats per minute) and/or hypoxemia (oxygen saturation <80%) are associated with increased mortality and/or intracranial hemorrhage. However, despite the accumulated evidence, the way in which oxygen should be supplemented in the first minutes after birth still has not yet been clearly established. The initial inspired fraction of oxygen and its adjustment within a safe arterial oxygen saturation range measured by pulse oximetry that avoids hyper-or-hypoxia is still a matter of debate. Herewith, we present a current summary aiming to assist the practical neonatologist who has to aerate the lung and establish an efficacious respiration in very preterm infants in the delivery room.

Animal models in neonatal resuscitation research: What can they teach us?

Animal models have made and continue to make important contributions to neonatal medicine. For example, studies in fetal sheep have taught us much about the physiology of the fetal-to-neonatal transition. However, whereas animal models allow multiple factors to be investigated in a logical and systematic manner, no animal model is perfect for humans and so we need to understand the fundamental differences in physiology between the species in question and humans. Although most physiological systems are well conserved between species, some small differences exist and so wherever possible the knowledge generated from preclinical studies in animals should be tested in clinical trials. However, with the rise of evidence-based medicine the distinction between scientific knowledge generation and evidence gathering has been confused and the two have been lumped together. This misunderstands the contribution that scientific knowledge can provide. Science should be used to guide the gathering of evidence by informing the design of clinical trials, thereby increasing their likelihood of success. While scientific knowledge is not evidence, in the absence of evidence it is likely to be the best option for guiding clinical practice.

Echocardiographic Evaluation of Transitional Circulation for the Neonatologists.

The hemodynamic changes during the first few breaths after birth are probably the most significant and drastic adaptation in the human life. These changes are critical for a smooth transition of fetal to neonatal circulation. With the cord clamping, lungs take over as the source of oxygenation from placenta. A smooth transition of circulation is a complex mechanism and primarily depends upon the drop in pulmonary vascular resistance (PVR) and increase in systemic vascular resistance (SVR). Understanding the normal transition physiology and the adverse adaptation is of utmost importance to the clinicians looking after neonates. It may have a significant influence on the presentation of congenital heart defects (CHDs) in infants. Bedside echocardiography may help in understanding the transition physiology, especially the hemodynamic changes and shunting across ductus arteriosus and foramen ovale, and it may play an important role in making judicious clinical decisions based upon the altered physiology.

Influence of Sex on Gestational Complications, Fetal-to-Neonatal Transition, and Postnatal Adaptation.

Fetal sex is associated with striking differences during in utero development, fetal-to-neonatal transition, and postnatal morbidity and mortality. Male sex fetuses are apparently protected while in utero resulting in a higher secondary sex rate for males than for females. However, during fetal-to-neonatal transition and thereafter in the newborn period, female exhibits a greater degree of maturation that translates into a better capacity to stabilize, less incidence of prematurity and prematurity-associated morbidities, and better long-term outcomes. The present review addresses the influence of sex during gestation and postnatal adaptation that includes the establishment of an adult-type circulation, the initiation of breathing, endurance when confronted with perinatal hypoxia ischemia, and a gender-related different response to drugs. The intrinsic mechanisms explaining these differences in the perinatal period remain elusive and further experimental and clinical research are therefore stringently needed if an individual oriented therapy is to be developed.

Afferent neural feedback overrides the modulating effects of arousal, hypercapnia and hypoxaemia on neonatal cardiorespiratory control.

KEY POINTS: Evidence obtained at whole animal, organ-system, and cellular and molecular levels suggests that afferent volume feedback is critical for the establishment of adequate ventilation at birth. As a result of the irreversible nature of the vagal ablation studies performed to date, it was difficult to quantify the roles of afferent volume input, arousal and changes in blood gas tensions on neonatal respiratory control. During reversible perineural vagal block, profound apnoeas and hypoxaemia and hypercarbia were observed, necessitating the termination of perineural blockade. Respiratory depression and apnoeas were independent of sleep state. We demonstrate that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. A change in sleep state and concomitant respiratory depression result from a lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period. ABSTRACT: Afferent volume feedback plays a vital role in neonatal respiratory control. Mechanisms for the profound respiratory depression and life-threatening apnoeas observed in vagally denervated neonatal animals remain unclear. We investigated the roles of sleep states, hypoxic-hypercapnia and afferent volume feedback on respiratory depression using reversible perineural vagal block during the early postnatal period. Seven lambs were instrumented during the first 48 h of life to record/analyse sleep states, diaphragmatic electromyograph, arterial blood gas tensions, systemic arterial blood pressure and rectal temperature. Perineural cuffs were placed around the vagi to attain reversible blockade. Postoperatively, during the awake state, both vagi were blocked using 2% xylocaine for up to 30 min. Compared to baseline values, pHa , Pao2 and Sao2 decreased and Paco2 increased during perineural blockade (P < 0.05). Four of seven animals exhibited apnoeas of ≥20 s requiring the immediate termination of perineural blockade. Breathing rates decreased from the baseline value of 53 ± 12 to 24 ± 20 breaths min-1 during blockade despite an increased Paco2 (P < 0.001). Following blockade, breathing patterns returned to baseline values despite marked hypocapnia ( Paco2 33 ± 3 torr; P = 0.03). Respiratory depression and apnoeas were independent of sleep states. The present study provides the much needed physiological evidence indicating that profound apnoeas and life-threatening respiratory failure in vagally denervated animals do not result from a lack of arousal or hypoxaemia. Rather, a change in sleep state and concomitant respiratory depression result from a lack of afferent volume feedback, which appears to be critical for the maintenance of normal breathing patterns and adequate gas exchange during the early postnatal period.

Mask Continuous Positive Airway Pressure Therapy with Simultaneous Extrauterine Placental Transfusion for Resuscitation of Preterm Infants - A Preliminary Study.

BACKGROUND: Delayed cord clamping or cord milking improves cardiovascular stability and outcome of preterm infants. However, both techniques may delay initiation of respiratory support. To allow lung aeration during cord blood transfusion, we implemented an extrauterine placental transfusion (EPT) approach. This study aimed to provide a detailed description of the EPT procedure and to evaluate its impact on the outcome of infants. METHODS: A retrospective analysis was performed comprising 60 preterm infants (220/7 to 316/7 weeks of gestation). Of these, 40 were transferred to the resuscitation unit with the placenta still connected to the infant. In this EPT group, continuous positive airway pressure support was initiated while, simultaneously, placental blood was transfused by holding the placenta 40-50 cm above the infant's heart. The cords of another 20 infants were clamped before respiratory support was started (standard group). Data on the infants' outcome were compared retrospectively. In a subgroup of 22 infants (n = 14 EPT, n = 8 standard), respiratory function monitor recordings were performed and both heart rates and SpO2 levels in the first 10 min of life were compared between groups. RESULTS: Although infants in the EPT group were lighter (EPT: 875 ± 355 g, standard: 1,117 ± 389 g; p = 0.02) and younger (266/7 weeks ± 19 days vs. 282/7 weeks ± 18 days; p = 0.045), there was no difference in neonatal outcome, including the incidence of intraventricular hemorrhage, bronchopulmonary disease, and red blood cell transfusions (all p > 0.1). Moreover, no differences in SpO2 levels and heart rates were observed in the infants whose resuscitations were recorded using a respiratory function monitor. CONCLUSIONS: In this retrospective analysis, EPT had no negative effects on the outcome of the infants, which warrants further evaluation in prospective randomized studies.

Transition from fetal to neonatal circulation: Modeling the effect of umbilical cord clamping.

Hemodynamics of the fetal to neonatal transition are orchestrated through complex physiological changes and results in cardiovascular adaptation to the adult biventricular circulation. Clinical practice during this critical period can influence vital organ physiology for normal newborns, premature babies and congenital heart defect patients. Particularly, the timing of the cord clamping procedure, immediate (ICC) vs. delayed cord clamping (DCC), is hypothesized to be an important factor for the transitory fetal hemodynamics. The clinical need for a quantitative understanding of this physiology motivated the development of a lumped parameter model (LPM) of the fetal cardio-respiratory system covering the late-gestation to neonatal period. The LPM was validated with in vivo clinical data and then used to predict the effects of cord clamping procedures on hemodynamics and vital gases. Clinical time-dependent resistance functions to simulate the vascular changes were introduced. For DCC, placental transfusion (31.3 ml) increased neonatal blood volume by 11.7%. This increased blood volume is reflected in an increase in preload pressures by ~20% compared to ICC, which in turn increased the cardiac output (CO) by 20% (COICC=993 ml/min; CODCC=1197 ml/min). Our model accurately predicted dynamic flow patterns in vivo. DCC was shown to maintain oxygenation if the onset of pulmonary respiration was delayed or impaired. On the other hand, a significant 25% decrease in oxygen saturations was observed when applying ICC under the same physiological conditions. We conclude that DCC has a significant impact on newborn hemodynamics, mainly because of the improved blood volume and the sustained placental respiration.

Prolonging in utero-like oxygenation after birth diminishes oxidative stress in the lung and brain of mice pups.

BACKGROUND: Fetal-to-neonatal transition is associated with oxidative stress. In preterm infants, immaturity of the antioxidant system favours supplemental oxygen-derived morbidity and mortality. OBJECTIVES: To assess if prolonging in utero-like oxygenation during the fetal-to-neonatal transition limits oxidative stress in the lung and brain, improving postnatal adaptation of mice pups. MATERIAL AND METHODS: Inspiratory oxygen fraction (FiO2) in pregnant mice was reduced from 21% (room air) to 14% (hypoxia) 8-12 h prior to delivery and reset to 21% 6-8 h after birth. The control group was kept at 21% during the procedure. Reduced (GSH) and oxidized (GSSG) glutathione and its precursors [γ-glutamyl cysteine (γ-GC) and L-cysteine (CySH)] content and expression of several redox-sensitive genes were evaluated in newborn lung and brain tissue 1 (P1) and 7 (P7) days after birth. RESULTS: As compared with control animals, the GSH/GSSG ratio was increased in the hypoxic group at P1 and P7 in the lung, and at P7 in the brain. In the hypoxic group a significant increase in the mRNA levels of NAD(P)H:quinone oxidoreductase 1 (noq1), Sulfiredoxin 1 (srnx1) and Glutathione Peroxidase 1 (gpx) was found in lung tissue at P1, as well as a significant increase in gpx in brain tissue at P7. CONCLUSIONS: Delaying the increase in tissue oxygenation to occur after birth reduces short-and-long-term oxidative stress in the lung. Similar yet more subtle effects were found in the brain. Apparently, the fetal-to-neonatal transition under hypoxic conditions appears to have protective qualities.