Systemic hemodynamics and pediatric lung disease: Mechanistic links and therapeutic relevance.

Chronic lung disease, also known as bronchopulmonary dysplasia affects thousands of infants worldwide each year. The impact on resources is second only to bronchial asthma, with lung function affected well into adolescence. Diagnostic and therapeutic constructs have almost exclusively focussed on pulmonary architecture (alveoli/airways) and pulmonary hypertension. Information on systemic hemodynamics indicates major artery thickness/stiffness, elevated systemic afterload and/or primary left ventricular dysfunction may play a part in a subset of infants with severe neonatal-pediatric lung disease. Understanding the underlying principles with attendant effectors would aid in identifying the pathophysiological course where systemic afterload reduction with angiotensin converting enzyme inhibitors could become the preferred treatment strategy over conventional pulmonary artery vasodilatation.

Vascular responsiveness to low-dose dexamethasone in extremely premature infants: Negative influence of fetal growth restriction.

Dexamethasone is frequently prescribed for preterm infants to wean from respiratory support and/or to facilitate extubation. This pre-post intervention prospective study ascertained the impact on clinical (respiratory support) and echocardiographic parameters after dexamethasone therapy in preterm FGR infants compared to AGA infants. Echocardiography was performed within 24 hours before the start and after completion of 10-day therapy. Parameters assessed included those reflecting pulmonary vascular resistance and right ventricular output. Seventeen FGR infants (birth gestation and birthweight 25.2±1.1 weeks and 497±92g) were compared with 22 AGA infants (gestation and birthweight 24.5±0.8 and 663±100g). Baseline respiratory severity score (mean airway pressure x fractional inspired oxygen) was comparable between the groups, (median [interquartile range] FGR: 10 [6, 13] vs AGA: 8±2.8, P=0.08). Pre-dexamethasone parameters of pulmonary vascular resistance (FGR: 0.19±0.03 vs AGA 0.2±0.03, P=0.16) and right ventricular output (FGR: 171±20 vs 174±17 ml/kg/min, P=0.6) were statistically comparable. At post-dexamethasone assessments, the decrease in respiratory severity score was significantly greater in AGA infants, (median [interquartile range] FGR: 10 [6, 13] to 9 [2.6, 13.5], P=0.009 vs AGA: 8±2.8 to 3±1, P<0.0001). Improvement in measures of pulmonary vascular resistance (time to peak velocity/right ventricular ejection time) was greater in AGA infants (FGR: 0.19±0.03 to 0.2±0.03, P=0.13 vs AGA 0.2±0.03 to 0.25±0.03, P<0.0001). The improvement in right ventricular output was significantly greater in AGA infants (171±20 to 190±21, P=0.014 vs 174±17 to 203±22, P<0.0001). This highlights differential cardiorespiratory responsiveness to dexamethasone in extremely preterm FGR infants, which may reflect the in-utero maladaptive state.

Molecular regulators of defective placental and cardiovascular development in fetal growth restriction.

Placental insufficiency is one of the major causes of fetal growth restriction (FGR), a significant pregnancy disorder in which the fetus fails to achieve its full growth potential in utero. As well as the acute consequences of being born too small, affected offspring are at increased risk of cardiovascular disease, diabetes and other chronic diseases in later life. The placenta and heart develop concurrently, therefore placental maldevelopment and function in FGR may have profound effect on the growth and differentiation of many organ systems, including the heart. Hence, understanding the key molecular players that are synergistically linked in the development of the placenta and heart is critical. This review highlights the key growth factors, angiogenic molecules and transcription factors that are common causes of defective placental and cardiovascular development.

Changes in respiratory mechanics in response to crystalloid infusions in extremely premature infants.

Extremely premature infants are at a higher risk of developing respiratory distress syndrome and circulatory impairments in the first few weeks of life. Administration of normal saline boluses to manage hypotension is a common practice in preterm infants. As a crystalloid, a substantial proportion might leak into the interstitium; most consequently the lungs in the preterm cohorts, putatively affecting ventilation. We downloaded and analyzed ventilator mechanics data in infants managed by conventional mechanical ventilation and administered normal saline bolus for clinical reasons. Data were downloaded for 30 min prebolus, 60 min during the bolus followed by 30 min postbolus. Sixteen infants (mean gestational age 25.2 ± 1 wk and birth weight 620 ± 60 g) were administered 10 mL/kg normal saline over 60 min. The most common clinical indication for saline was hypotension. No significant increase was noted in mean blood pressure after the saline bolus. A significant reduction in pulmonary compliance (mL/cmH2O/kg) was noted (0.43 ± 0.07 vs. 0.38 ± 0.07 vs. 0.33 ± 0.07, P = 0.003, ANOVA). This was accompanied by an elevation in the required peak inspiratory pressure to deliver set volume-guarantee (19 ± 2 vs. 22 ± 2 vs. 22 ± 3 mmHg, P < 0.0001, ANOVA), resulting in a higher respiratory severity score. Normal saline infusion therapy was associated with adverse pulmonary mechanics. Relevant pathophysiologic mechanisms might include translocation of fluid across pulmonary capillaries affected by low vascular tone and heightened permeability in extremes of prematurity, back-pressure effects from raised left atrial volume due to immature left-ventricular myocardium; complemented by the effect of cytokine release from positive pressure ventilation.NEW & NOTEWORTHY Administration of saline boluses is common in premature infants although hypovolemia is an uncommon underlying cause of hypotension. This crystalloid can redistribute into pulmonary interstitial space. In the presence of an immature myocardium and diastolic dysfunction, excess fluid can also be "edemagenic." This study on extremely premature infants (25 wk gestation) noted adverse influence on respiratory physiology after saline infusion. Clinicians need to choose judiciously and reconsider routine use of saline boluses in premature infants.

Influence of accelerated arterial aging in growth-restricted cohorts on adult-onset cardiovascular diseases.

Epidemiologists have long documented a higher risk of adult-onset cardiovascular diseases (CVDs) such as stroke, hypertension, and coronary artery disease, as well as mortality from circulatory causes in low birth-weight cohorts (poor in utero substrate supply). Utero-placental insufficiency and in utero hypoxemic state-induced alterations in arterial structure and compliance are important initiating factors for adult-onset hypertension. The mechanistic links between fetal growth restriction and CVD include decreased arterial wall elastin-to-collagen ratio, endothelial dysfunction, and heightened renin-angiotensin-aldosterone system (RAAS). Systemic arterial thickness on fetal ultrasound and vascular changes in placental histopathology in growth restricted cohorts indicate fetal/developmental origins of adult-onset circulatory diseases. Similar findings of impaired arterial compliance have been noticed across age groups (neonates through to adults). Such changes augment what occurs as "normal arterial aging," resulting in accelerated arterial aging. Data from animal models suggest that hypoxemia-associated vascular adaptations enacted in utero are region specific, reflecting long-term vascular pathology. In this review, we explore the influence of birthweight and prematurity on blood pressure and arterial stiffness, demonstrating impaired arterial dynamics in growth-restricted cohorts across age groups, explain how early arterial aging influences adult-onset CVDs, describe pathophysiology data from experimental models and finally, discuss interventions which may influence aging by way of altering various cellular and molecular mechanisms of arterial aging. Age-appropriate interventions which have noted efficacy include prolonged breastfeeding and high polyunsaturated fatty acids dietary intake. Targeting the RAAS seems a promising approach. New data indicate activation of sirtuin 1 and maternal resveratrol may have beneficial effects.

Cardiovascular responses to mild perinatal asphyxia in growth-restricted preterm lambs.

Growth-restricted neonates have worse outcomes after perinatal asphyxia, with more severe metabolic acidosis than appropriately grown neonates. The cardiovascular physiology associated with fetal growth restriction (FGR) may alter their response to asphyxia. However, research on asphyxia in FGR is limited. Here we compared cardiovascular hemodynamics in preterm FGR and control lambs during mild perinatal asphyxia. We induced FGR in one twin at 89 days gestation (term 148 days), while the other served as a control. At 126 days gestation, lambs were instrumented to allow arterial blood pressure and regional blood flow recording, and then mild perinatal asphyxia was induced by umbilical cord clamping, and resuscitation followed neonatal guidelines. FGR lambs maintained carotid blood flow (CBF) for 7 min, while control lambs rapidly decreased CBF (P < 0.05). Fewer growth-restricted lambs needed chest compressions for return of spontaneous circulation (ROSC) (17 vs. 83%, P = 0.02). The extent of blood pressure overshoot after ROSC was similar, but it took longer for MAP to return to baseline in FGR lambs (18.83 ± 0.00 vs. 47.67 ± 0.00 min, P = 0.003). Growth-restricted lambs had higher CBF after ROSC (P < 0.05) and displayed CBF overshoot, unlike control lambs (P < 0.03). In conclusion, preterm growth-restricted lambs show resilience during perinatal asphyxia based on prolonged CBF maintenance and reduced need for chest compressions during resuscitation. However, CBF overshoot after ROSC may increase the risk of cerebrovascular injury in FGR.NEW & NOTEWORTHY Preterm growth-restricted lambs maintain carotid blood flow for longer than control lambs during asphyxia and have a lower requirement for chest compressions than control lambs during resuscitation. Preterm growth-restricted, but not control, lambs displayed an overshoot in carotid blood flow following return of spontaneous circulation.

Cardiovascular decline in offspring during the perinatal period in an ovine model of fetal growth restriction.

Fetal growth restriction (FGR) increases the risk cardiovascular disease (CVD) in adulthood. Placental insufficiency and subsequent chronic fetal hypoxemia are causal factors for FGR, leading to a redistribution of blood flow that prioritizes vital organs. Subclinical signs of cardiovascular dysfunction are evident in growth-restricted neonates; however, the mechanisms programming for CVD in adulthood remain unknown. This study aimed to determine the potential mechanisms underlying structural and functional changes within the heart and essential (carotid) and nonessential (femoral) vascular beds in growth-restricted lambs. Placental insufficiency was surgically induced in ewes at 89 days gestational age (dGA, term = 148dGA). Three age groups were investigated: fetal (126dGA), newborn (24 h after preterm birth), and 4-wk-old lambs. In vivo and histological assessments of cardiovascular indices were undertaken. Resistance femoral artery function was assessed via in vitro wire myography and blockade of key vasoactive pathways including nitric oxide, prostanoids, and endothelium-dependent hyperpolarization. All lambs were normotensive throughout the first 4 wk of life. Overall, the FGR cohort had more globular hearts compared with controls (P = 0.0374). A progressive decline in endothelium-dependent vasodilation was demonstrated in FGR lambs compared with controls. Further investigation revealed that impairment of the prostanoid pathway may drive this reduction in vasodilatory capacity. Clinical indicators of CVD were not observed in our FGR lambs. However, subclinical signs of cardiovascular dysfunction were present in our FGR offspring. This study provides insight into potential mechanisms, such as the prostanoid pathway, that may warrant therapeutic interventions to improve cardiovascular development in growth-restricted newborns.NEW & NOTEWORTHY Our findings provide novel insight into the potential mechanisms that program for cardiovascular dysfunction in growth-restricted neonates as our growth-restricted lambs exhibited a progressive decline in endothelium-dependent vasodilation in the femoral artery between birth and 4 wk of age. Subsequent analyses indicated that this reduction in vasodilatory capacity is likely to be mediated by the prostanoid pathway and prostanoids could be a potential target for therapeutic interventions for fetal growth restriction (FGR).

Early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol: a retrospective cohort study.

BACKGROUND: Paracetamol is commonly used for analgesia and patent ductus arteriosus (PDA) treatment in preterm infants. We aimed to evaluate early neurodevelopmental outcomes of extreme preterm infants exposed to paracetamol during their neonatal admission. METHODS: This retrospective cohort study included surviving infants born at <29 weeks gestation, or with a birth weight of <1000 grams. Neurodevelopmental outcomes studied were early cerebral palsy (CP) or high risk of CP diagnosis, Hammersmith Infant Neurological Examination (HINE) score and Prechtl General Movement Assessment (GMA) at 3-4 months corrected age. RESULTS: Two hundred and forty-two infants were included, of which 123 were exposed to paracetamol. After adjusting for birth weight, sex and chronic lung disease, there were no significant associations between paracetamol exposure and early CP or high risk of CP diagnosis (aOR 1.46, 95% CI 0.61, 3.5), abnormal or absent GMA (aOR 0.82, 95% CI 0.37, 1.79) or HINE score (adjusted ß -0.19, 95% CI -2.39, 2.01). Subgroup analysis stratifying paracetamol exposure into <180 mg/kg or ≥180 mg/kg cumulative dose found that neither had significant effects on outcomes. CONCLUSIONS: In this cohort of extreme preterm infants, no significant association was found between exposure to paracetamol during the neonatal admission and adverse early neurodevelopment. IMPACT: Paracetamol is commonly used in the neonatal period for analgesia and patent ductus arteriosus treatment in preterm infants, although prenatal paracetamol use has been associated with adverse neurodevelopmental outcomes. Exposure to paracetamol during the neonatal admission was not associated with adverse early neurodevelopment at 3-4 months corrected age in this cohort of extreme preterm infants. The findings from this observational study is consistent with the small body of literature supporting the lack of association between neonatal paracetamol exposure and adverse neurodevelopmental outcomes in preterm infants.

Cardiorespiratory adaptation to low-dose dexamethasone for lung disease in extremely preterm infants: A prospective echocardiographic study.

The cardiovascular impact of dexamethasone (Dex) is not well understood. Most data are obtained from a 6 week, high-dose regimen, and are limited to findings of hypertension and cardiac hypertrophy. The present study ascertained the impact of low-dose Dex on cardiac indices when administered to extremely preterm infants for lung disease. A pre-post intervention prospective echocardiographic (Echo) study was undertaken, with cardiac assessments performed before and within 24 h after completion of first course of therapy (10 day regimen, cumulative 0.89 mg kg-1 ). Thirty infants with a gestational age of 24.6 ± 1.1 weeks and birthweight of 612 ± 125 g, respectively, were studied. The age at Dex administration was 20 ± 9 days. Fractional inspired oxygen decreased from 0.7 ± 0.23 to 0.35 ± 0.14 (P < 0.001). Patent ductus arteriosus was noted in 20 infants at Echo1. At Echo2, the ductal diameter decreased from 2.16 ± 0.8 to 1.1 ± 0.8 mm (P = 0.0003), with complete closure in 7/20 (35%). A reduction in left pulmonary artery end-diastolic velocity was noted (17 ± 12 to 9 ± 10 cm s-1 , P < 0.001). Pulmonary vascular resistance decreased (increased time to peak velocity/right ventricular ejection time, 0.2 ± 0.03 to 0.23  ± 0.03, P = 0.0001) and right ventricular systolic performance improved (tricuspid annular plane systolic excursion, 4.9 ± 0.8 to 5.5 ± 0.9 mm, P = 0.02). No significant changes in fractional shortening and left ventricular mass were noted. A significant increase in blood pressure was noted. As a percentage of pre-treatment baseline, the mean increase for systolic blood pressure was 20.3% (95% confidence interval = 14-26) on day 2 (P = 0.008). Low-dose Dex influenced cardiovascular parameters related to pulmonary circulation. KEY POINTS: Corticosteroid therapy is frequently used in preterm infants who are dependent on ventilator support. Echocardiographic studies in infants administered a 6 week course of steroids have noted left ventricular hypertrophy, outlet obstruction and hypertension, but no information is available on right heart indices. The cardiopulmonary effects of the current, significantly lesser cumulative dose (10 day regimen, commonly described as 'DART') have not been evaluated. The present study noted a significant influence on ductal and pulmonary circulation indices. Left heart architecture and function was maintained, whereas a significant but transient increase in blood pressure was noted.

Fetal growth restriction and neonatal-pediatric lung diseases: Vascular mechanistic links and therapeutic directions.

Bronchopulmonary dysplasia (BPD) is the most common respiratory sequela of prematurity, and infants born with fetal growth restriction (FGR) are disproportionately represented in BPD statistics, as factors which affect somatic growth may also affect pulmonary growth. Effects of in-utero hypoxia underlying FGR on lung parenchymal architecture predisposing to BPD are well documented, but the pulmonary vascular constructs are not well appreciated. Disruption of angiogenesis during critical periods of lung growth impairs alveolarization, contributing to BPD pathogenesis. Pulmonary artery thickness/stiffness has been noted in FGR in the initial postnatal weeks, and also in well-grown infants with established BPD. The lack of waveform cushioning by the major arteries exposes the pulmonary resistance vessels to higher pulsatile stress, thereby accelerating microvascular disease. Reactive oxygen species, increased sympathetic activity and endothelial dysfunction are common mediators in FGR and BPD; each putative targets for prevention and/or therapeutics using interleukin (IL)-1 receptor antagonist (IL-1Ra), melatonin or inhibition of renin-angiotensin-aldosterone system. While BPD is the archetypal respiratory disease of infancy, effects of FGR on pulmonary function are long-term, extending well into childhood. This narrative links FGR in very/extremely preterm infants with BPD through the vascular affliction as a mechanistic and potentially, therapeutic pathway. Our objectives were to depict the burden of disease for FGR and BPD amongst preterm infants, portray vascular involvement in the placenta in FGR and BPD cohorts, provide high resolution vascular ultrasound information in both cohorts with a view to address therapeutic relevance, and lastly, link this information with paediatric age-group lung diseases.

Mitral valve Doppler for cardiac output assessment in preterm neonates.

INTRODUCTION: Cardiac output (CO) assessment in neonates is commonly done by echocardiography. It is unclear which is the best site to measure the left ventricular (LV) outflow tract for CO assessment (the aortic valve [AV] aortic sinus [AS] or the sinotubular junction [STJ]). In the normal heart, the blood flow entering the LV equals the blood ejected from it. Therefore, measuring the blood flow into the LV through the mitral valve (MV) is an alternative way to measure CO. METHODS: In stable preterm infants the MV CO was compared with the right ventricular (RV) CO and the three ways to measure LV CO, in 30 stable preterm neonates. Interobserver variability for MV CO was established. RESULTS: In the 30 neonates studied, MV CO was best correlated and had a minimal bias to the RV CO and LV CO measured at the STJ. Left ventricular CO measured at the AV and AS had significant bias relative to RV CO and MV CO. MV CO inter-observer variability was similar to other echocardiographic CO assessment methods. CONCLUSION: MV CO may be used as an alternative way to assess CO. The STJ may be the optimal site to measure LV outflow tract.

Nucleated Red Blood Cells as Markers of Perinatal Adaptation in Preterm Neonates Receiving Minimally Invasive Surfactant Therapy.

OBJECTIVE: The study aimed to assess the association of nucleated red blood cells (NRBC), a surrogate of intrauterine hypoxia, and elevated pulmonic vascular resistance (E-PVR) and oxygen requirement after minimally invasive surfactant therapy (MIST). STUDY DESIGN: Retrospective study of a cohort of preterm neonates that received MIST in a single unit. RESULTS: NRBC were measured in 65 of 75 (87%) neonates administered MIST during the period. In total, 22 of 65 (34%) infants had pre-MIST echocardiography (ECHO).Neonates with elevated NRBC (predefined as >5 × 109/L, n = 16) required higher post-MIST fraction of inspired oxygen (FiO2) than neonates with normal NRBC (<1 × 109/L, n = 17; FiO2 = 0.31 ± 0.10 and 0.24 ± 0.04, respectively, p = 0.02).NRBC correlated positively with % of time in right to left ductal shunt (r = 0.51, p = 0.052) and inversely with right ventricular stroke volume (r = -0.55, p = 0.031) and time to peak velocity to right ventricular ejection time ratio (r = -0.62, p < 0.001). CONCLUSION: Elevated NRBC are associated with elevated FiO2 after MIST and elevated E-PVR. Intrauterine hypoxia may impact postnatal circulatory adaptations and oxygen requirement. KEY POINTS: · Post-MIST FiO2 requirements are significantly higher in infants with elevated NRBC.. · NRBC correlates positively with elevated PVR in neonates requiring.. · Intrauterine hypoxia may play a role in postnatal circulatory adaptations in neonates with RDS..

Fifteen-minute consultation: How to spot serious heart disease in the newborn.

Congenital heart disease (CHD) is common and important as it remains a leading cause of neonatal morbidity and appreciable mortality. Prenatal diagnosis, the presence of a murmur, cyanosis, tachypnoea and/or poor or differential peripheral pulses raise the suspicion of CHD aided by differential pre/postductal saturations. Yet even serious CHD may not be considered when such clues are absent. Nevertheless, there are clinical cues which may alert the clinician to the possibility of a significant CHD which may lead to an early and accurate diagnosis and appropriate intervention to achieve best results. This paper addresses these issues which become especially difficult if caring for infants away from facilities provided by tertiary centres. Tachypnoea on the first postnatal day is generally non-cardiac in origin. Exceptions include large arteriovenous fistulae and/or 'pump' (ventricular) failure. In addition, attention is drawn to two important confounding factors in the newborn, namely the patency of the ductus arteriosus and the initially high pulmonary vascular resistance, both of which alter and may mask the clinical findings of a serious cardiac abnormality. An appreciation of the physiological changes that occur in early infancy will aid the clinician's understanding of CHD as it affects the newborn.

Early detection of significant congenital heart disease: The contribution of fetal cardiac ultrasound and newborn pulse oximetry screening.

Fetal cardiac and newborn pulse oximetry screening has greatly facilitated the detection of cardiac abnormalities, which may be serious with potentially dire neonatal consequences. The prenatal diagnosis of a serious cardiac abnormality allows the attending obstetrician to organise the much safer in-utero transfer of the fetus for delivery at a tertiary centre, particularly if there is evidence of a duct-dependent lesion that may require the infusion of Prostaglandin E1 to maintain duct patency pending surgical intervention. Newborn pulse oximetry alerts the paediatrician that the baby may have a significant cardiac abnormality, which warrants further elucidation prior to discharge, rather than for the baby to represent unwell a few days later. Despite these advances, serious cardiac abnormalities may be missed on screening. Their detection then falls back onto the clinical acumen of the attending paediatrician/family physician to review the history, carefully elicit and evaluate the clinical signs further aided by whatever investigations that may be available at the birthing hospital, frequently less resourced than the tertiary centres. At the outset, a brief synopsis is provided of the clinical findings that may point to a cardiac abnormality. That is followed by a critical review of the accuracy of prenatal and newborn pulse oximetry screening with emphasis on the lesions that may be missed. Suggestions are made as to how to improve the diagnostic accuracy.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Impact of Skin-to-Skin Parent-Infant Care on Preterm Circulatory Physiology.

OBJECTIVES: To ascertain the impact of skin-to-skin care between parents and infants on cardiac function and cerebral blood flow in preterm infants. STUDY DESIGN: We undertook a prospective study of 40 self-ventilating preterm infants at a quaternary center and assessed cardiac performance and cerebral blood flow. Assessments were carried out two hours before skin-to-skin care and then 60 minutes after skin-to-skin care (with the infant still on parent and turned supine). RESULTS: Infants were 30.5 ± 0.6 weeks' gestational age and 1378 ± 133 g birthweight. Axillary temperature noted a nonsignificant increase during skin-to-skin care from 36.7 ± 0.07°C to 36.9 ± 0.07°C (P = .07). Cardiac contractility (right ventricular fractional area change [26.5% ± 0.3% vs 27.8% ± 0.4; P < .001] and tricuspid annular plane systolic excursion [0.73 ± 0.03 cm vs 0.77 ± 0.03 cm; P = .02]) increased significantly, coincident with decreased measures of pulmonary vascular resistance. An increase in systemic cardiac output was associated with increased cerebral blood flow and reduced middle cerebral artery resistive index (0.81 ± 0.02 vs 0.74 ± 0.02; P = .0001). CONCLUSIONS: We documented a significant circulatory beneficial adaptation to a common neonatal practice. These findings align with previously documented physiologic benefits in cardiorespiratory stability and cardiac rhythm in preterm infants, and may be mediated through modulation of the autonomic nervous system.

Effects of Maternal Sildenafil Treatment on Vascular Function in Growth-Restricted Fetal Sheep.

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.

Diuretic use in infants with developing or established chronic lung disease: A practice looking for evidence.

AIM: The objective was to assess respiratory efficacy of hydrochlorothiazide and spironolactone and ascertain any adverse effects. METHODS: Data from 2014 to 2018 was analysed for infants <28 weeks' gestational age (GA) administered oral diuretics. Impact on respiratory support, weight gain and electrolyte status was assessed as a pre-post intervention study. RESULTS: Of 491 infants, 117 (24%) were administered diuretics for evolving or established bronchopulmonary dysplasia. GA and birthweight of the cohort were 25.7 ± 1.1 weeks and 779 ± 172 g, respectively. Median (interquartile range) chronological age and GA at the start of diuretics was 45 (22, 62) days and 32.1 (30.1, 35.1) weeks, respectively. In 71/117 (61%) infants, diuretics were started at <36 weeks GA. Of them 63 (88.7%) went on to develop bronchopulmonary dysplasia. Median duration of diuretics was 38 (18-52) days. Modest improvement was noted in respiratory parameters (ventilator pressure (cm of H2 O), 8.8 ± 0.4 vs. 8.8 ± 0.5, P = 0.39, oxygen requirement (%), 32 ± 1 vs. 30 ± 1, P = 0.07 and pO2 (mm Hg) 34.5 ± 1.3 vs. 36.6 ± 1, P = 0.04. Ninety-eight (84%) infants developed hyponatraemia (<135 mmol/L); sodium supplements were administered in 58/98 (59%) infants. In one third infants, phosphate levels dropped below 1.8 mmol/L, needing supplementation. Weight gain (g/kg/day) slowed down significantly (18.2 ± 2.1 to 10 ± 2.9, P = <0.001). CONCLUSIONS: Use of diuretics was associated with modest improvements in respiratory support requirements but was associated with significant electrolyte abnormalities and slowdown in weight gain (or weight loss).

Preterm growth restriction and bronchopulmonary dysplasia: the vascular hypothesis and related physiology.

KEY POINTS: Approximately 5-10% pregnancies are affected by fetal growth restriction. Preterm infants affected by fetal growth restriction have a higher incidence of bronchopulmonary dysplasia. The present study is the first to measure pulmonary artery thickness and stiffness. The findings show that impaired vasculogenesis may be a contributory factor in the higher incidence of bronchopulmonary dysplasia in preterm growth restricted infants. The study addresses the mechanistic link between fetal programming and vascular architecture and mechanics. ABSTRACT: Bronchopulmonary dysplasia is the most common respiratory sequelae of prematurity and histopathologically features fewer, dysmorphic pulmonary arteries. The present study aimed to characterize pulmonary artery mechanics and cardiac function in preterm infants with fetal growth restriction (FGR) compared to those appropriate for gestational age (AGA) in the early neonatal period. This prospective study reviewed 40 preterm infants between 28 to 32 weeks gestational age (GA). Twenty infants had a birthweight <10th centile and were compared with 20 preterm AGA infants. A single high resolution echocardiogram was performed to measure right pulmonary arterial and right ventricular (RV) indices. The GA and birthweight of FGR and AGA infants were 29.8 ± 1.3 vs. 30 ± 0.9 weeks (P = 0.78) and 923.4 g ± 168 vs. 1403 g ± 237 (P < 0.001), respectively. Assessments were made at 10.5 ± 1.3 days after birth. The FGR infants had significantly thicker right pulmonary artery inferior wall (843.5 ± 68 vs. 761 ± 40 µm, P < 0.001) with reduced pulsatility (51.6 ± 7.6 µm vs. 59.7 ± 7.5 µm, P = 0.001). The RV contractility [fractional area change (28.7 ± 3.8% vs 32.5 ± 3.1%, P = 0.001), tricuspid annular peak systolic excursion (TAPSE) (5.2 ± 0.3% vs. 5.9 ± 0.7%, P = 0.0002) and myocardial performance index (0.35 ± 0.03 vs. 0.28 ± 0.02, P < 0.001)] was significantly impaired in FGR infants. Significant correlation between RV longitudinal contractility (TAPSE) and time to peak velocity/RV ejection time (measure of RV afterload) was noted (r2  =  0.5, P < 0.001). Altered pulmonary vascular mechanics and cardiac performance reflect maladaptive changes in response to utero-placental insufficiency. Whether managing pulmonary vascular disease will alter clinical outcomes remains to be studied prospectively.

Fetal growth restriction is associated with an altered cardiopulmonary and cerebral hemodynamic response to surfactant therapy in preterm lambs.

BACKGROUND: Efficacy of surfactant therapy in fetal growth restricted (FGR) preterm neonates is unknown. METHODS: Twin-bearing ewes underwent surgery at 105 days gestation to induce FGR in one twin by single umbilical artery ligation. At 123-127 days, catheters and flow probes were implanted in pulmonary and carotid arteries to measure flow and pressure. Lambs were delivered, intubated and mechanically ventilated. At 10 min, surfactant (100 mg kg-1) was administered. Ventilation, oxygenation, and hemodynamic responses were recorded for 1 h before euthanasia at 120 min. Lung tissue and bronchoalveolar lavage fluid was collected for analysis of surfactant protein mRNA and phosphatidylcholines (PCs). RESULTS: FGR preterm lambs were 26% lighter than appropriate for gestational age (AGA) lambs and had baseline differences in lung mechanics and pulmonary blood flows. Surfactant therapy reduced ventilator and oxygen requirements and improved lung mechanics in both groups, although a more rapid improvement in compliance and tidal volume was observed in AGA lambs. Surfactant administration was associated with decreased mean pulmonary and carotid blood flow in FGR but not AGA lambs. No major differences in surfactant protein mRNA or PC levels were noted. CONCLUSIONS: Surfactant therapy was associated with an altered pulmonary and cerebral hemodynamic response in preterm FGR lambs.