Extended period of ventilation before delayed cord clamping augments left-to-right shunting and decreases systemic perfusion at birth in preterm lambs.

Previous studies have suggested that an extended period of ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. However, it is unknown whether this greater rise in PA flow is accompanied by increases in left ventricular (LV) output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale (FO), with decreased systemic arterial perfusion. Using an established preterm lamb birth transition model, this study compared the effect of a short (∼40 s, n = 11), moderate (∼2 min, n = 11) or extended (∼5 min, n = 12) period of initial mechanical lung ventilation before DCC on flow probe-derived perinatal changes in PA flow, LV output, total systemic arterial blood flow, ductal shunting and FO shunting. The LV output was relatively stable during initial ventilation but increased after DCC, with similar responses in all groups. Systemic arterial flow patterns displayed only minor differences during brief and moderate periods of initial ventilation and were similar after DCC. However, an increase in PA flow was augmented with an extended initial ventilation (P < 0.001), owing to an earlier onset of left-to-right ductal and FO shunting (P < 0.001), and was accompanied by a pronounced reduction in total systemic arterial flow (P = 0.005) that persisted for 4 min after DCC (P ≤ 0.039). These findings suggest that, owing to increased left-to-right shunting and a greater reduction in systemic arterial perfusion, an extended period of ventilation before DCC does not result in greater perinatal circulatory benefits than shorter periods of initial ventilation in the birth transition. KEY POINTS: Previous studies suggest that an extended period of initial ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. It is unknown whether this greater rise in PA flow is accompanied by an increased left ventricular output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale, with decreased systemic arterial perfusion. Anaesthetized preterm fetal lambs instrumented with central arterial flow probes underwent a brief (∼40 s), moderate (∼2 min) or extended (∼5 min) period of ventilation before DCC. Perinatal changes in left ventricular output were similar in all groups, but extended initial ventilation augmented both perinatal increases in PA flow, owing to earlier onset and greater left-to-right ductal and foramen ovale shunting, and perinatal reductions in total systemic arterial perfusion. Extended ventilation before DCC does not confer a greater perinatal circulatory benefit than shorter periods of initial ventilation.

Molecular mechanisms regulating extracellular matrix-mediated remodeling in the ductus arteriosus.

Progressive remodeling throughout the fetal and postnatal period is essential for anatomical closure of the ductus arteriosus (DA). Internal elastic lamina interruption and subendothelial region widening, elastic fiber formation impairment in the tunica media, and intimal thickening are distinctive features of the fetal DA. After birth, the DA undergoes further extracellular matrix-mediated remodeling. Based on the knowledge obtained from mouse models and human disease, recent studies revealed a molecular mechanism of DA remodeling. In this review, we focus on matrix remodeling and regulation of cell migration/proliferation associated with DA anatomical closure and discuss the role of prostaglandin E receptor 4 (EP4) signaling and jagged1-Notch signaling as well as myocardin, vimentin, and secretory components including tissue plasminogen activator, versican, lysyl oxidase, and bone morphogenetic proteins 9 and 10.

Using omics to breathe new life into our understanding of the ductus arteriosus oxygen response.

The ductus arteriosus (DA) connects the aorta to the pulmonary artery (PA), directing placentally oxygenated blood away from the developing lungs. High pulmonary vascular resistance and low systemic vascular resistance facilitate shunting of blood in utero from the pulmonary to the systemic circulation through the widely patent DA, thereby optimizing fetal oxygen (O2) delivery. With the transition from fetal (hypoxia) to neonatal (normoxia) oxygen conditions, the DA constricts while the PA dilates. This process often fails in prematurity, promoting congenital heart disease. Impaired O2-responsivness in the DA promotes persistent ductus arteriosus (PDA), the most common form of congenital heart disease. Knowledge of DA oxygen sensing has greatly advanced in the past few decades, however we still lack a complete understanding of the sensing mechanism. The genomic revolution of the past two decades has facilitated unprecedented discovery in every biological system. This review will demonstrate how multiomic integration of data generated from the DA can breathe new life into our understanding of the DA's oxygen response.

Coarctation of the aorta: Prenatal assessment, postnatal management and neonatal outcomes.

Coarctation of the aorta (Coa) is a potentially life threatening diagnosis. It occurs in 0.3 per 1000 live births and accounts for 6-8% of all infants with congenital heart defects. Neonates with severe Coa may be completely asymptomatic at birth, as the ductus arteriosus can provide flow to the lower body. Those who are not diagnosed prenatally may be diagnosed only after constriction of the ductus arteriosus, when they present in cardiogenic shock. This group has a higher risk for mortality and morbidity relative to those diagnosed prenatally. Despite the increasing practice of universal pulse oximetry screening, many cases with significant coarctation of the aorta still go undiagnosed in the newborn period. In this article, we present the pathophysiology, diagnosis, presentation, treatment and outcomes of Coa.

Physiological fetal vascular shunts and failure to regress: what the radiologist needs to know.

The fetal circulation is characterized by the presence of three physiological vascular shunts - the ductus arteriosus, the foramen ovale and the ductus venosus. Acting in concert, these shunts preferentially stream blood flow in a pattern that maximizes efficiency of blood oxygenation by the maternofetal unit. Shortly following the transition to extrauterine life, a quick and predetermined succession of events results in closure of these embryological structures with consequent establishment of postnatal vascular flow patterns. While this transition is often seamless, the physiological shunts of the fetus occasionally fail to regress. Such failure to regress can occur in isolation or in association with other congenital malformations. This failed regression challenges the circulatory physiology of the neonate and might have implications for the optimum functioning of several organ systems. When symptomatic, these shunts are treated. Interventions, when undertaken, might be medical, endovascular or surgical. The radiologist's role continues to expand in the assessment of these shunts, in providing a roadmap for treatment and in prompt identification of treatment-related complications. This review is to familiarize radiologists with the embryology, pre- and post-treatment imaging appearances, and associated complications of persistent fetal vascular shunts.

Open or closed: Changes in ductus arteriosus flow patterns at birth using 4D flow MRI in newborn piglets.

The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White-Landrace-Duroc piglets (n = 34) spanning four age groups: term-9 days, term-3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow-term-9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter-term-9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R2  = 0.32, p = 0.004), and left (R2  = 0.33, p = 0.003) and right (R2  = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p < 0.05). Expanded use of these techniques in preterm animal models will aid in providing new understandings of normal versus abnormal DA transition, as well as to test the effectiveness of related clinical interventions.

A new index of ultrasonography for estimating cerebral circulation in newborn infants.

PURPOSE: To quantitatively estimate the influence of ductal shunt on cerebral blood flow and establish a new index of ultrasonography for estimating cerebral circulation without the influence of ductal shunt in newborn infants. METHODS: We retrospectively examined the records of anterior cerebral artery (ACA) and left pulmonary artery (LPA) blood flow velocity curves recorded by pulsed Doppler ultrasonography within 6 h after birth in 123 newborn infants without asphyxia (normal group) and in 31 newborn infants with asphyxia (asphyxia group). RESULTS: In the normal group, the resistance index (RI) of the ACA showed a positive correlation with the ratio of LPA diastolic-to-systolic flow velocities (LPAD/LPAS) (P < 0.001, r = 0.58), and the estimated RI (eRI) of the ACA was calculated using the following formula: Y = 0.47X + 0.67 (Y estimated RI; X LPAD/LPAS). In the asphyxia group, the RI of the ACA showed a weak correlation to base excess (BE) (P < 0.05, r = 0.46). The eRI of the ACA was calculated by the LPAD/PLAS in the asphyxia group, and the difference between the RI and eRI showed a better correlation to BE than RI (P < 0.001, r = 0.64). CONCLUSION: We determined the relation between cerebral blood flow RI and ductal shunt, and (RI - eRI) may be a new useful ultrasonographic index indicating cerebral circulation without the influence of ductal shunt in newborn infants.

Vasoactivity of magnesium sulfate in chicken ductus arteriosus.

Prenatal treatment with magnesium sulfate (MgSO4) has neuroprotective effects in very preterm infants but its use has been associated with an increased rate of patent ductus arteriosus (DA). MgSO4 is a vasodilator and thus may exert a direct relaxant effect in the DA. We aimed to investigate the vasoactive effects of MgSO4 in the DA using the chicken embryo as experimental model. DA rings from 15-d (E15), 17-d (E17) and 19-d (E19) chicken embryos (total incubation: 21-d) were mounted in a wire myograph for isometric tension recordings. Exposure of DA rings to 21% O2 induced a tonic contraction which was relaxed by MgSO4 (2.4 - 7.2 mmol L-1) in a concentration-dependent manner (mean maximal relaxation E19: 51.4%, SE 6.3; EC50: 3.5 mmol L-1, SE 0.7). The relaxation evoked by MgSO4 was not significantly different between E15, E17 and E19 DA and was not affected by removal of the endothelium or by the presence of the nitric oxide synthase inhibitor L-NAME, the soluble guanylate cyclase inhibitor ODQ, or the cyclooxygenase inhibitor indomethacin. In contrast, when the DA rings were incubated in Ca2+-free solution, or in the presence of inhibitors of L-type Ca2+ channels (nifedipine), or large-conductance Ca2+-activated K+ (BKCa) channels (iberiotoxin), MgSO4-induced relaxation was impaired. Preincubation of the DA rings with MgSO4 concentrations ranging from 0 to 6.0 mmol L-1 did not significantly affect O2-induced contraction that was only impaired by a concentration of 7.2 mmol L-1. In conclusion, MgSO4 induced endothelium-independent relaxation of chicken DA and this relaxation appeared to be mediated through stimulation of BKCa channels and blockade of transmembrane flux of extracellular Ca2+. However, O2-induced DA contraction was only impaired by suprapharmacological concentrations of MgSO4 (> 6.0 mmol L-1). Therefore, our data suggest that the higher incidence of patent DA in preterm infants exposed to MgSO4 is unlikely to be due to a direct pharmacological effect of the drug on the DA.

Normal variants of ductus venosus spectral Doppler flow patterns in normal pregnancies.

Objectives: Ductus venosus (DV) Doppler examinations in pregnancy have a widespread use for several important indications and play a crucial role in order to determine the fetal well-being. DV is usually visualized by the color Doppler mapping. We observed the instantaneous spectral flow type changes in pulsed Doppler examinations in spite of performing with the correct technique published by several authors. The variability of the pattern makes the sonographer/physician to be unsure for the correct placements of the sample gate despite fulfilling the all the criteria required for the vessel sampling. It is aimed in the study to define variations of the normal DV spectral flow types in the duration of the pulsed Doppler examinations instead of in a single cardiac cycle in normal pregnancies.Methods: This prospective study was conducted between January 2016 and February 2017. Wide-band Doppler technique was used for color mapping of the DV. Normal spectral Doppler waveforms in pregnancies are classified as types. When DV spectral flow pattern was not in the standard type, the spectral flow patterns were obtained from not only the umbilical artery and/or middle cerebral artery. Maximum and minimum blood flow velocities in the umbilical vein are measured. All Doppler examinations are performed by a single experienced specialist (CG), who had been certificated for DV flow and Doppler examinations by the Fetal Medicine Foundation.Results: A total of seven types of flow patterns were recorded during the study period and DV flow patterns were divided into two main categories as classic flow pattern and the other patterns. The classic pattern was observed in 160 (99.4%) cases in the first trimester, 495 (94.1%) cases in the second trimester and 206 (60.8%) cases in the third trimester.Conclusions: We think that the fetal circulation is complicated more than estimated. There might be some endocrine agents released in the instantaneous physiologic reactions and changing the venous return abruptly or due to decreasing of the cardiac output directed to the placenta after 34 weeks influence the volume of the circulating blood in the fetus and so thereby the flow velocities instantaneously. The spectral waveform recognition approach is not reliable to identify if the DV spectral Doppler pattern is not the classic (standard) type and the DV should be visualized by wide-band color Doppler techniques particularly in the third trimester for the pulsed Doppler examinations. Studies are needed to evaluate the normal spectral variants of the flows correlated with the physiological compensatory mechanisms.

Longitudinal Doppler references for monochorionic twins and comparison with singletons.

OBJECTIVES: To construct monochorionic (MC) twin-specific longitudinal Doppler references for umbilical artery pulsatility index (UA-PI), middle cerebral artery (MCA) PI and peak systolic velocity (PSV) and ductus venosus (DV) PI derived from a strictly selected cohort of uncomplicated MC twins. The secondary aim of the study was to compare our findings with singleton reference charts. METHODS: A retrospective evaluation was made of all consecutive uncomplicated MC twin pregnancies referred to our Unit from 2010 to 2018. Fortnightly serial examinations were performed of UA-PI, MCA-PI, MCA-PSV and DV-PI, according with the clinical protocol, from 20 to 37 weeks of gestation. We included cases with at least four ultrasound examinations, delivery at our hospital and complete neonatal follow up. A two-step method was used to trace the estimated centile curves: estimation of the median was performed with appropriate fractional polynomials by a multilevel model and estimation of the external centiles through the residuals (quantile regression). The comparison with singletons was made by plotting the references derived from the present study on the referred charts commonly used for singletons. RESULTS: The study group comprised 150 uncomplicated MC twin pairs. Estimated centiles (3rd, 5th, 10th, 50th, 90th, 95th, 97th) of UA-PI, MCA-PI, MCA-PSV and DV-PI in function of the gestational age are presented. The comparison with singletons showed substantial differences, with higher UA-PI and lower MCA-PI and PSV median values in MC twins. Median DV PI values were similar to the values for singletons, while the upper centiles were higher in MC twins. CONCLUSIONS: This study sets out MC twin-specific longitudinal references for UA-PI, MCA-PI, MCA-PSV and DV-PI derived from the largest series of uncomplicated MC twin pregnancies presently available. The comparison with singleton reference values underscores the deviation from physiology that is intrinsic to these unique pregnancies and supports the need for MC twin-specific charts.

Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063.

Glucose-stimulated insulin secretion from pancreatic ß-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of ß-cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.

Associations of measures of systemic blood flow used in a randomized trial of delayed cord clamping in preterm infants.

OBJECTIVE: To determine associations of low superior vena cava (SVC) flow (≤55 ml/kg/min) and low right ventricular output (RVO) (≤150 ml/kg/min) in preterm infants. DESIGN/METHODS: An observational study in infants <30 weeks gestation randomized to receive immediate (<10 s) or delayed cord clamping (DCC) (≥60 s). RESULTS: The study enrolled 265 infants with a mean (SD) gestation 28 (2) weeks. Eighty-six (33%) infants had low SVC flow and 81 (31%) infants had low RVO. In multivariate analysis, low SVC flow was associated with gestation; low RVO was associated with DCC, gender and 5-minute Apgar; whereas mean RVO was negatively associated with both FiO2 and mean airway pressure (MAP) at 9 h and 24 h. Low SVC flow was associated with ductus arteriosus (DA) treatment. Infants with low RVO had higher mortality on univariate analysis, but this was not significant after adjusting for gestation. CONCLUSIONS: SVC flow was associated with gestation, whilst RVO was associated with placental transfusion, gender, condition at birth, and early respiratory adaptation. Compared to infants with normal values, more infants with low SVC flow were treated for DA, but infants with low RVO had no significant difference in mortality or morbidity.

Understanding the Pathophysiology, Implications, and Treatment Options of Patent Ductus Arteriosus in the Neonatal Population.

BACKGROUND: Patent ductus arteriosus (PDA) is the persistence of a fetal shunt between the pulmonary artery and the aorta. This structure normally closes in the first 3 days after birth; however, closure is delayed in up to 80% of infants born at 25 to 28 weeks of gestation. Persistent PDA results in pulmonary overcirculation and systemic hypoperfusion. PURPOSE: The purpose of this article is to review pathophysiology and treatment options for PDA. METHODS: A literature review was conducted using PubMed, CINAHL, and Google Scholar (2013-2018). Search terms included neonate, PDA, pathophysiology, pharmacotherapy, nursing, ligation, indomethacin, ibuprofen, and acetaminophen (paracetamol). RESULTS: Optimal treatment remains contentious. Options include conservative/medical, pharmacologic, and surgical management. Conservative/medical management includes mild fluid restriction, increased airway pressures, and supportive care. Pharmacologic treatment is accomplished using indomethacin, ibuprofen, or acetaminophen. Surgical intervention is by direct closure or by percutaneous ligation. Treatment may be prophylactic, presymptomatic, or symptomatic. Long-term morbidities associated with PDA include chronic lung disease, retinopathy of prematurity, and neurodevelopmental delay. IMPLICATIONS FOR RESEARCH: Absence of a universal scoring system for severity of PDA limits accuracy of comparisons among research studies. Lack of a consistent definition also makes it difficult to aggregate data for meta-analyses. Adoption of a consistent scoring system for hemodynamic significance would facilitate comparisons of outcomes among research studies. IMPLICATIONS FOR PRACTICE: Clinicians should be aware of treatment options for PDA and their implications on neonatal outcomes. For nurses, anticipation of possible side effects is important for performance of focused assessments.

B-type natriuretic peptide prevents postnatal closure of ductus arteriosus by both vasodilation and anti-remodeling in neonatal rats.

The physiologic process of postnatal ductus arteriosus (DA) closure consists of vasoconstriction followed by vascular remodeling. We have recently reported that B-type natriuretic peptide (BNP), a potent vasodilator, also has anti-remodeling effects in pulmonary vasculature. However, its effects on DA have not been elucidated. We investigated whether BNP can prevent DA closure, and if so, the underlying mechanisms. Using in vivo studies, we examined effects of BNP (10 mg/kg, ip at birth) on DA closure in neonatal rats within 4 h after birth. We found that in control rats, the DA spontaneously closed at 4 h with a decreased DA diameter, enhanced intimal thickening, and luminal occlusion. BNP prevented DA closure at 4 h with a preserved DA diameter, attenuated intimal thickening, and preserved luminal patency. Ex vivo, BNP attenuated oxygen-induced vasoconstriction of isolated DA rings of newborn rats. These vasodilating effects were blunted by Rp-8-Br-PET-cGMPS, a cGMP inhibitor. In vitro, BNP inhibited angiotensin II (Ang II)-induced proliferation and migration of DA smooth muscle cells (DASMCs). BNP inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production and calcium overload in DASMCs. Finally, BNP inhibited Ang II-induced ERK1/2 activation. These in vitro effects were antagonized by Rp-8-Br-PET-cGMPS. In conclusion, BNP prevents postnatal DA closure by both vasodilation and anti-remodeling through the cGMP pathway. The mechanisms underlying anti-remodeling effects include anti-poliferation and anti-migration, with attenuation of mitochondrial ROS production and intracellular calcium and ERK1/2 signaling. Therefore, the BNP/cGMP pathway can be a promising therapeutic target for clinical management of DA patency.

Molecular Mechanisms for Regulating Postnatal Ductus Arteriosus Closure.

The ductus arteriosus (DA) connects the main pulmonary artery and the aorta in fetal circulation and closes spontaneously within days after birth in normal infants. Abnormal patent DA (PDA) causes morbidities and mortality, especially in preterm infants. Closure of the DA is a complex interactive process involving two events: functional and anatomic closure. Functional closure by smooth muscle contraction was achieved through the regulatory factors of vaso-reactivity. These factors include oxygen sensing system, glutamate, osmolality, prostaglandin E2, nitric oxide, and carbon monoxide. Anatomic closure by vascular remodeling involved several vascular components including endothelium, extracellular matrix, smooth muscle cells, and intraluminal blood cells. Despite advances in understanding of PDA pathogenesis, the molecular mechanism for regulation of DA closure is complex and not fully understood. In this article we review recent evidence regarding the molecular mechanisms of DA closure.

Transcriptional profiling of the ductus arteriosus: Comparison of rodent microarrays and human RNA sequencing.

DA closure is crucial for the transition from fetal to neonatal life. This closure is supported by changes to the DA's signaling and structural properties that distinguish it from neighboring vessels. Examining transcriptional differences between these vessels is key to identifying genes or pathways responsible for DA closure. Several microarray studies have explored the DA transcriptome in animal models but varied experimental designs have led to conflicting results. Thorough transcriptomic analysis of the human DA has yet to be performed. A clear picture of the DA transcriptome is key to guiding future research endeavors, both to allow more targeted treatments in the clinical setting, and to understand the basic biology of DA function. In this review, we use a cross-species cross-platform analysis to consider all available published rodent microarray data and novel human RNAseq data in order to provide high priority candidate genes for consideration in future DA studies.

Comparative physiology of the ductus arteriosus among vertebrates.

The ductus arteriosus is typically viewed as a mammalian fetal blood vessel providing a right-to-left shunt of right ventricular outflow away from the lungs and to the systemic circuit, that must close at birth. This review provides a wider comparative examination of the ductus arteriosus in lungfish, reptiles, birds, and mammals. The ductus arteriosus evolved with the lung in the ancestors of the lungfish as a connection between the pulmonary arteries and dorsal aorta. During embryonic development, reptiles, birds, and mammals all possess either one or two paired ductus arteriosi that provide a fetal shunt of blood away from the lungs. Differences in the fetal circulatory arrangement are seen between these groups and this influences the importance of the ductus arteriosus as an embryonic shunt. The ductus arteriosus from lungfish and tetrapod vertebrates is an oxygen sensitive blood vessel, with shared conserved pathways involved in oxygen sensing. By expanding studies into more comparative models such as lungfish or developing birds a better understanding of the physiology of the ductus arteriosus can be developed.

Hemodynamic Effects on Systemic Blood Flow and Ductal Shunting Flow after Loading Dose of Intravenous Caffeine in Preterm Infants according to the Patency of Ductus Arteriosus.

BACKGROUND: In preterm infants, caffeine citrate is used to stimulate breathing before they are weaned from mechanical ventilation and to reduce the frequency of apnea. In recent studies, effects of caffeine on the cardiovascular system have been emphasized in preterm infants with patent ductus arteriosus (PDA). METHODS: This study aimed to assess the short-term hemodynamic effects on systemic blood flow and ductal shunting flow after loading standard doses of intravenous caffeine in preterm infants. Echocardiographic studies were performed by a single investigator, before and at 1 hour and 4 hours after an intravenous infusion of a loading dose as 20 mg/kg caffeine citrate for 30 minutes. RESULTS: In 25 preterm infants with PDA, left ventricular output decreased progressively during 4 hours after caffeine loading. Superior vena cava (SVC) flow decreased and ductal shunting flow increased at 1 hour and then recovered at 4-hour to baseline values. A diameter of PDA significantly decreased only at 4-hour after caffeine loading. There were no significant changes of these hemodynamic parameters in 29 preterm infants without PDA. CONCLUSION: In preterm infants with PDA, a standard intravenous loading dose of 20 mg/kg caffeine citrate was associated with increasing ductal shunting flow and decreasing SVC flow (as a surrogate for systemic blood flow) 1 hour after caffeine loading, however, these hemodynamic parameters recovered at 4 hours according to partial constriction of the ductus arteriosus. Close monitoring of hemodynamic changes would be needed to observe the risk for pulmonary over-circulation or systemic hypo-perfusion due to transient increasing ductal shunting flow during caffeine loading in preterm infants with PDA.

Influence of ductus arteriosus on peripheral muscle oxygenation and perfusion in neonates.

OBJECTIVE: In neonates, a patent ductus arteriosus (DA) may be associated with severe complications. We used near-infrared spectroscopy (NIRS) with venous occlusion to investigate the influence of an open DA on peripheral muscle oxygenation/perfusion in preterm neonates. APPROACH: We analyzed secondary outcome parameters collected as part of prospective observational studies. NIRS measurements were performed between the first and third day of life. Arterial oxygen saturation (SaO2) and heart rate (HR) were monitored by pulse oximetry on the ipsilateral foot. Venous occlusion was performed with a blood pressure cuff on the thigh. Tissue oxygenation index (TOI), hemoglobin flow (Hbflow), oxygen delivery (DO2), oxygen consumption (VO2), mixed venous oxygenation (SvO2), and fractional oxygen extraction (FOE) were assessed. Echocardiography was performed within plus/minus 6 h from NIRS measurements. MAIN RESULTS: Twenty-eight neonates were included. In neonates with open DA (n = 15), the FOE was significantly higher (p = 0.046). DA diameter correlated negatively with SvO2 (r = -0.413, p = 0.032) and positively with FOE (r = 0.417, p = 0.030). In neonates with open DA, SaO2 was significantly lower (p = 0.041). DA diameter correlated negatively with SaO2 (r = -0.377, p = 0.048) and positively with HR (r = 0.489, p = 0.010). SIGNIFICANCE: Our results showed that an open DA influences peripheral muscle oxygenation in preterm neonates.

The effect of breathing on ductus arteriosus blood flow directly after birth.

Spontaneous breathing at birth influences ductus arteriosus (DA) flow. This study quantifies the effect of breathing on DA shunting directly after birth. In healthy term infants born by elective cesarean section, simultaneous measurements of DA shunting and tidal volumes during spontaneous breathing were performed at 2-5, 5-8, and 10-13 min after birth. Eight infants with a mean (SD) gestational age of 40 (1) weeks and 3216 (616) grams were studied. Inspiratory tidal volume was 5.8 (3.3-7.7), 5.7 (4.0-7.1), and 5.2 (4.3-6.1) mL/kg at 2-5, 5-8, and 10-13 min. The velocity time integral of left-to-right shunting significantly increased during inspiration when compared to expiration (8.4 (5.2) vs. 3.7 (2.3) cm, 8.9 (4.4) vs. 5.6 (3.4) cm, and 14.0 (6.7) vs. 8.4 (6.9) cm; all p < 0.0001) at 2-5, 5-8, and 10-13 min, respectively. In contrast, right-to-left shunting was not different between inspiration and expiration at 2-5 and 10-13 min (11.1 (2.4) vs. 11.1 (2.6) cm and 10.7 (2.3) vs. 10.6 (3.0) cm; p > 0.05), but there was a small increase at 5-8 min (12.1 (2.4) vs. 10.8 (2.9) cm; p = 0.001) during expiration. CONCLUSION: Directly after birth, ductal shunting is influenced by breathing effort, predominantly with an increase in left-to-right shunt due to inspiration. What is Known: • Spontaneous breathing at birth influences ductus arteriosus flow and pulmonary blood flow. • Crying causes a significant increase in left-to-right ductus arteriosus shunting. What is New: • Left-to-right ductus arteriosus shunting increases during inspiration compared to expiration. • Breathing is important for ductal shunting and contributes to pulmonary blood flow.