Cerebral Oximetry Monitoring in Extremely Preterm Infants.

BACKGROUND: The use of cerebral oximetry monitoring in the care of extremely preterm infants is increasing. However, evidence that its use improves clinical outcomes is lacking. METHODS: In this randomized, phase 3 trial conducted at 70 sites in 17 countries, we assigned extremely preterm infants (gestational age, <28 weeks), within 6 hours after birth, to receive treatment guided by cerebral oximetry monitoring for the first 72 hours after birth or to receive usual care. The primary outcome was a composite of death or severe brain injury on cerebral ultrasonography at 36 weeks' postmenstrual age. Serious adverse events that were assessed were death, severe brain injury, bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, and late-onset sepsis. RESULTS: A total of 1601 infants underwent randomization and 1579 (98.6%) were evaluated for the primary outcome. At 36 weeks' postmenstrual age, death or severe brain injury had occurred in 272 of 772 infants (35.2%) in the cerebral oximetry group, as compared with 274 of 807 infants (34.0%) in the usual-care group (relative risk with cerebral oximetry, 1.03; 95% confidence interval, 0.90 to 1.18; P = 0.64). The incidence of serious adverse events did not differ between the two groups. CONCLUSIONS: In extremely preterm infants, treatment guided by cerebral oximetry monitoring for the first 72 hours after birth was not associated with a lower incidence of death or severe brain injury at 36 weeks' postmenstrual age than usual care. (Funded by the Elsass Foundation and others; SafeBoosC-III ClinicalTrials.gov number, NCT03770741.).

Assessment of Myocardial Function in Infants of Mothers with Gestational Diabetes Mellitus Using Deformation Imaging over the First Year of Age.

OBJECTIVE: To assess serial myocardial performance and pulmonary vascular resistance (PVR) in infants of mothers with gestational diabetes mellitus (GDM) over the first year of life. STUDY DESIGN: This was a prospective, observational study. Echocardiography was performed at birth, 6 months, and 1 year of age. Pulmonary artery acceleration time and left ventricular (LV) eccentricity index provided surrogate measurements of PVR. Biventricular function was assessed by tissue Doppler imaging and deformation analysis. RESULTS: Fifty infants of mothers with GDM were compared with 50 controls with no difference in gestation (38.9 ± 0.8 weeks vs 39.3 ± 0.9 weeks; P = .05) or birthweight (3.55 ± 0.49 kg vs 3.56 ± 0.41 kg; P = .95). At 1 year of age, the pulmonary artery acceleration time was lower (70 ± 11 vs 79 ± 10; P = .01) in the GDM group. LV global longitudinal strain (24.7 ± 1.9 vs 28.8 ± 1.8 %; P < .01), LV systolic strain rate (1.8 ± 0.2 vs 2.1 ± 0.3 1/s; P < .01), and RV free wall strain (31.1 ± 4.8 vs 34.6 ± 3.9 %; P < .01) were lower in the GDM cohort at 1 year of age (all P values adjusted for gestation, mode of delivery, and maternal body mass index). CONCLUSIONS: Our findings demonstrate higher indices of PVR and lower biventricular function in infants of mothers with GDM compared with controls at each time point assessed in this study over the first year of life.

The impact of a PDA on tissue oxygenation and haemodynamics following a blood transfusion in preterm infants.

BACKGROUND: To examine the impact of PRBC transfusion on pulmonary vascular resistance (PVR), systemic vascular resistance and myocardial function using echocardiography and cerebral and splanchnic tissue oxygenation using near-infrared spectroscopy (NIRS) in premature babies with and without a PDA. METHODS: A prospective observational study of premature infants born <1500 g in receipt of PRBC transfusions beyond 10 days of age. Echocardiography and NIRS monitoring were performed at baseline, during the transfusion and 24 h after transfusion. RESULTS: Thirty infants with a median gestation of 26.4 [24.8-28.0] weeks were enrolled. Ten infants had a PDA. Following transfusion, a significant decrease in PVR markers occurred in all infants. Right ventricular (RV) function increased following transfusion in the PDA closed group only. Cerebral oxygen saturation increased following transfusion in all infants. Babies in the PDA open group had significantly lower splanchnic oxygen saturations at baseline compared to the PDA closed group which persisted over the study period and were unaltered by transfusion. CONCLUSIONS: PRBC transfusion lowers PVR irrespective of PDA status. Those with a PDA demonstrated a lack of improvement in RV function and splanchnic oxygenation highlighting the impact a PDA has on the neonatal circulation. IMPACT: The presence or absence of the PDA imposes differential effects on splanchnic oxygenation during red blood cell (PRBC) transfusion in the premature population. This is the first study to assess the impact of the PDA on splanchnic oxygenation via near-infrared spectroscopy (NIRS) during red blood cell transfusion in premature neonates. New insights have been found into the impact of PRBC transfusion on pulmonary vascular resistance, right ventricular function, cerebral and splanchnic oxygenation in the presence and absence of a PDA and emphasises the ongoing impact of ductal patency on gut oxygenation.

Nutrition of the preterm infant with persistent ductus arteriosus: existing evidence and practical implications.

The persistence of a patent ductus arteriosus (PDA) is a common condition in preterm infants with a prevalence inversely proportional to gestational age. PDA is associated with mild-to-severe gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which represent a major challenge for the nutritional management in preterm infants. In this context, the Section on Nutrition, Gastroenterology and Metabolism and the Circulation Section of the European Society for Pediatric Research have joined forces to review the current knowledge on nutritional issues related to PDA in preterm infants. The aim of the narrative review is to discuss the clinical implications for nutritional practice. Because there is little literature on postnatal nutrition and PDA in preterm infants, further research with well-designed studies on this topic is urgently needed. Guidelines should also be developed to clearly define the implementation and course of enteral nutrition and the target nutritional intake before, during, and after pharmacologic or surgical treatment of PDA, when indicated. IMPACT: Persistent ductus arteriosus (PDA) is associated with gastrointestinal complications such as feeding intolerance, gastrointestinal perforation, and necrotizing enterocolitis, which pose a major challenge to the nutritional management of preterm infants. In PDA infants, fluid restriction may lead to inadequate nutrient intake, which may negatively affect postnatal growth and long-term health. The presence of PDA does not appear to significantly affect mesenteric blood flow and splanchnic oxygenation after enteral feedings. Initiation or maintenance of enteral nutrition can be recommended in infants with PDA.

Neonatal sepsis and cardiovascular dysfunction I: mechanisms and pathophysiology.

The highest incidence of sepsis across all age groups occurs in neonates leading to substantial mortality and morbidity. Cardiovascular dysfunction frequently complicates neonatal sepsis including biventricular systolic and/or diastolic dysfunction, vasoregulatory failure, and pulmonary arterial hypertension. The haemodynamic response in neonatal sepsis can be hyperdynamic or hypodynamic and the underlying pathophysiological mechanisms are heterogeneous. The diagnosis and definition of both neonatal sepsis and cardiovascular dysfunction complicating neonatal sepsis are challenging and not consensus-based. Future developments in neonatal sepsis management will be facilitated by common definitions and datasets especially in neonatal cardiovascular optimisation. IMPACT: Cardiovascular dysfunction is common in neonatal sepsis but there is no consensus-based definition, making calculating the incidence and designing clinical trials challenging. Neonatal cardiovascular dysfunction is related to the inflammatory response, which can directly target myocyte function and systemic haemodynamics.

Inhaled nitric oxide in preterm neonates with preterm prelabour rupture of membranes, a systematic review.

AIM: To perform a systematic literature review to determine the effect of inhaled nitric oxide (iNO) on oxygenation, mortality and morbidity in preterm neonates with preterm prelabour rupture of membranes (PPROM) and early hypoxaemic respiratory failure (HRF). METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Web of Science, Zetoc and ProQuest were searched. Studies including neonates <34 weeks' gestation with PPROM, oligohydramnios or pulmonary hypoplasia and HRF in the first 28 days of life treated with iNO were included. Studies were critically appraised and assessed for potential risk of bias using standardised checklists. RESULTS: Six hundred and two records remained after duplicates were removed. Seven studies were included in the critical appraisal process. Quality of available evidence was very low to low. Six studies described an improvement in oxygenation after commencement of iNO. One hundred and three of 284 (36%) neonates exposed to iNO died. Seventy-seven of 92 (84%) neonates that had an echocardiogram performed before commencement of iNO had pulmonary hypertension (PH) present. CONCLUSION: iNO may improve oxygenation when standard care fails. Improvement in oxygenation is likely associated with increase in survival. Survival may lead to an increase in morbidity. Efficacy of iNO in this cohort is likely secondary to relatively high prevalence of PH.

Assessment of myocardial function in infants conceived by assisted reproductive technologies using deformation imaging over the first year of age: A cohort study.

BACKGROUND AND AIM: There is emerging evidence of cardiovascular remodeling and functional impairment in individuals conceived via Assisted Reproductive Technologies (ART). The aim of this study was to serially assess myocardial function and pulmonary hemodynamic measurements in infants conceived via ART over the first year of age and to compare them to a cohort of spontaneously conceived controls. METHODS: This was a prospective, observational study. Echocardiography was performed at Day 2, 6 months and 1 year of age. Biventricular function was assessed by deformation analysis. Pulmonary artery acceleration time (PAAT) and left ventricular (LV) eccentricity index (LVEI) provided surrogate measures of pulmonary vascular resistance (PVR). RESULTS: Fifty infants conceived via ART were compared to 50 spontaneously conceived controls. There were no differences in baseline infant demographics between the two groups. At 1 year of age right ventricular (RV) basal and RV mid cavity diameters were higher in the ART group. PAATi was lower and LVEI higher in the ART group at 6 months and 1 year. In the ART group, LV global longitudinal strain, LV systolic strain rate, LV early diastolic strain rate and RV free wall strain were lower on Day 2, 6 months, and 1 year of age in comparison to the control group (all p < .05). Within the ART group, on linear regression, maternal age, the type of ART treatment or egg characteristics did not influence PAAT or deformation measurements. CONCLUSION: Our findings suggest that greater cardiovascular surveillance of ART conceived infants may be warranted.

Noise exposure exceeded safe limits during neonatal care and road transport but was reduced by active noise cancelling.

AIM: Noise levels above 45 dB in a neonatal intensive care unit (NICU) and 60 dB during neonatal transport are recognised hazards, but protective equipment is not standard. We measured noise levels in both settings, with and without noise protection. METHODS: Peak sound and equivalent continuous sound levels were measured in a NICU and during road transport, at a mannequin's ear and inside and outside the incubator. Recordings were made without protective earwear, with noise protecting earmuffs and with active noise cancelling headphones. RESULTS: In the NICU, the peak levels at the ear, and inside and outside the incubator, were 61, 68 and 76 dB. The equivalent continuous sound levels were 45, 54 and 59 dB. During road transport, the respective levels were 70, 77 and 83 dB and 54, 62 and 68 dB. In the NICU, 80% of environmental peak noise reached the ear and this was reduced to 78% with earmuffs and 75% with active noise cancelling. The respective figures during transport were 87% without protection and 72% with active noise cancelling, with an unexpected increase for ear muffs. CONCLUSION: Noise levels exceeded safe limits in the NICU and during transport, but active noise cancelling reduced exposure.

Relationship Between Postnatal Pulmonary Arterial Pressure and Altered Diastolic Function in Neonates with Down Syndrome.

OBJECTIVE: To assess the influence of diastolic dysfunction on the evolution of pulmonary hypertension in neonates with Down Syndrome over the early newborn period. STUDY DESIGN: This was a prospective observational cohort study. Echocardiography was performed three times over the first week of life in both Down syndrome and control cohorts. Measurements of pulmonary arterial pressure in addition to left ventricular (LV) and right ventricular systolic and diastolic function were collected. RESULTS: Seventy babies with Down syndrome and 60 control infants were enrolled. Forty-eight of the infants with Down syndrome (69%) were born with congenital heart disease (CHD). Echocardiography surrogates of pulmonary hypertension and myocardial function remained significantly impaired in the Down syndrome group in comparison with control infants (all P < .01). In the Down syndrome group, LV early diastolic strain rate was independently associated with measures of pulmonary hypertension while controlling for gestational age, cesarean delivery, and the presence of CHD (P < .01). CONCLUSIONS: Intrinsic LV diastolic impairment is directly associated with higher indices of pulmonary hypertension in infants with Down syndrome and may be a contributing factor to its evolution.

Infants with Down syndrome and congenital heart disease have altered peri-operative immune responses.

BACKGROUND: Infants with Down syndrome (DS) have an altered immune response. We aimed to characterise the inflammatory response in infants with DS and congenital heart disease (CHD) peri-operatively in comparison to infants with CHD and a normal chromosomal complement, and to healthy infants pre-operatively. METHODS: Infants with DS/CHD, infants without DS but with CHD (CHD only) and healthy infants were prospectively recruited and serial serum cytokines evaluated peri-operatively using multiplex ELISA: tumour necrosis factor (TNF)-α and TNF-ß; interferon (IFN)-γ, interleukin (IL)-1α, IL-2, IL-6, IL-8, IL-18, IL-1ß, IL-10, and IL-1ra; vascular endothelial growth factor (VEGF); granulocyte macrophage colony-stimulating factor (GM-CSF); and erythropoietin (EPO). RESULTS: Ninety-four infants were recruited including age-matched controls (n = 10), DS/CHD (n = 55), and CHD only (n = 29). Children with DS/CHD had significantly lower concentrations of several cytokines (IL-10, IL-6, IL-8, IL-1ß, VEGF) in the pre- and post-operatively vs CHD only and controls. EPO and GM-CSF were significantly higher in DS/CHD (p value <0.05). CONCLUSIONS: Children with DS/CHD had significantly lower concentrations of several cytokines compared to controls or children with CHD only. EPO and GM-CSF were significantly higher in children with DS/CHD. The assessment of the immune response may be suitable for the predictable clinical outcomes in these children. IMPACT: This study demonstrated that children with Down syndrome (DS) and congenital heart disease (CHD) have significant alterations in pro-inflammatory and anti-inflammatory immune responses peri-operatively. These changes may contribute to adverse clinical outcomes, including sepsis, chylothorax, and autoimmunity. They may impact the pathogenesis and outcome post-operatively and long term in this population. Children with DS and CHD have significantly lower cytokine concentrations, increased EPO and GM-CSF, and decreased VEGF pre- and post-operatively. Assessing their inflammatory state peri-operatively may facilitate the development of a predictive model that can inform tailored management of these infants using novel therapies including immunomodulation.

Platelets in pediatric and neonatal sepsis: novel mediators of the inflammatory cascade.

Sepsis, a dysregulated host response to infection, has been difficult to accurately define in children. Despite a higher incidence, especially in neonates, a non-specific clinical presentation alongside a lack of verified biomarkers has prevented a common understanding of this condition. Platelets, traditionally regarded as mediators of haemostasis and thrombosis, are increasingly associated with functions in the immune system with involvement across the spectrum of innate and adaptive immunity. The large number of circulating platelets (approx. 150,000 cells per microlitre) mean they outnumber traditional immune cells and are often the first to encounter a pathogen at a site of injury. There are also well-described physiological differences between platelets in children and adults. The purpose of this review is to place into context the platelet and its role in immunology and examine the evidence where available for its role as an immune cell in childhood sepsis. It will examine how the platelet interacts with both humoral and cellular components of the immune system and finally discuss the role the platelet proteome, releasate and extracellular vesicles may play in childhood sepsis. This review also examines how platelet transfusions may interfere with the complex relationships between immune cells in infection. IMPACT: Platelets are increasingly being recognised as important "first responders" to immune threats. Differences in adult and paediatric platelets may contribute to differing immune response to infections. Adult platelet transfusions may affect infant immune responses to inflammatory/infectious stimuli.

Survey highlighting the lack of consensus on diagnosis and treatment of patent ductus arteriosus in prematurity.

To gain insight in the availability of guidelines, diagnostic criteria, and treatment strategies and whether clinical equipoise regarding optimal treatment for patent ductus arteriosus (PDA) in prematurity is present. We hypothesized that (co-)authors of PDA-related papers were more likely to screen for a PDA and would treat earlier and more aggressively. An international internet-based survey between September 2019 and March 2020 in which we collected (1) baseline characteristics; (2) availability of guidelines; (3) screening strategy for PDA; (4) diagnostic criteria for hemodynamic significance; (5) treatment strategy; and (6) metrics of treatment efficacy. Finally, ten clinical equipoise statements were posed on a Likert scale. In total, 144 surveys were sent, of which 71/144 (49%) surveys could be analyzed with 56/71 (79%) fully completed surveys. The respondents, mainly neonatologists in a level III neonatal intensive care unit, of whom 36/71 (51%) had (co-)authored a publication on the PDA, highlighted a lack of national guidelines, heterogeneous approach to screening strategies, and marked variability in diagnostic criteria to assess hemodynamic significance, treatment strategies and effect measurement. No major significant differences were observed between respondents who did or did not (co-)author a publication on the PDA. Respondents who screened for PDA scored significantly higher on the need for screening, early and aggressive treatment. Remarkably, the scores of all statements regarding clinical equipoise varied widely.   Conclusions: Our survey highlights the lack of guidelines and enormous heterogeneity in current practice. Current evidence is not robust enough to harmonize current treatment strategies into (inter)national guidelines. What is Known: • Patent ductus arteriosus (PDA) incidence is inversely related to gestational age. • Although early pharmacological treatment induces PDA closure, optimal treatment is debated due to the lack of beneficial effects on outcome. What is New: • In the absence of (inter)national guidelines, diagnostic and treatment strategies are heterogeneous and contradictory, even in a selected hemodynamically- interested group. • Different PDA screening strategies did, while PDA publication status did not, show significant differences in treatment strategy and responses to equipoise statements.

The role of the calibrated automated thrombogram in neonates: describing mechanisms of neonatal haemostasis and evaluating haemostatic drugs.

Premature infants are at high risk of haemorrhage and thrombosis. Our understanding of the differences between the neonatal and adult haemostatic system is evolving. There are several limitations to the standard coagulation tests used in clinical practice, and there is currently a lack of evidence to support many of the transfusion practices in neonatal medicine. The evaluation of haemostasis is particularly challenging in neonates due to their limited blood volume. The calibrated automated thrombogram (CAT) is a global coagulation assay, first described in 2002, which evaluates both pro- and anti-coagulant pathways in platelet-rich or platelet-poor plasma. In this review, the current applications and limitations of CAT in the neonatal population are discussed.Conclusion: CAT has successfully elucidated several differences between haemostatic mechanisms in premature and term neonates compared with adults. Moreover, it has been used to evaluate the effect of a number of haemostatic drugs in a pre-clinical model. However, the lack of evidence of CAT as an accurate predictor of neonatal bleeding, blood volume required and the absence of an evidence-based treatment algorithm for abnormal CAT results limit its current application as a bedside clinical tool for the evaluation of sick neonates. What is Known: • The Calibrated automated thrombogram (CAT) is a global coagulation assay which evaluates pro- and anti-coagulant pathways. • CAT provides greater information than standard clotting tests and has been used in adults to evaluate bleeding risk. What is New: • This review summarises the physiological differences in haemostasis between neonates and adults described using CAT. • The haemostatic effect of several drugs has been evaluated in neonatal plasma using CAT.

Multi-organ dysfunction scoring in neonatal encephalopathy (MODE Score) and neurodevelopmental outcomes.

AIM: Neonatal encephalopathy (NE) is associated with an increased risk of multi-organ injury. The lack of standardised definitions for multi-organ dysfunction in NE hinders accurate quantification of these complications. METHODS: A simple multi-organ dysfunction in neonatal encephalopathy scoring (MODE) system was created to include the cardiovascular, respiratory, gastrointestinal, haematological and neurological systems with a maximum score of 15. The MODE score was then compared with the grade of NE, Bayley Scales of Infant Development (Bayley-III) at 2 years of age and mortality. The Bayley score was used as it gave an objective score making it easier to compare the MODE score. Bayley score of <90 and/or abnormal MRI as an adverse outcome. RESULTS: Infants with perinatal asphyxia (PA:n = 85) were prospectively enrolled (PA only n = 9; NE I = 23; NE II = 42; NE III = 11). Infants with higher MODE scores were significantly more likely to have moderate/severe NE (NE II/III: median scores (IQR) 7(5-10) versus mild NE 2 (1-3); p-value < 0.001) The MODE score was highly predictive of mortality (AUC 0.96, p-value = 0.002). Infants who had an abnormal neurological examination at discharge or abnormal Bayley-III scores had significantly higher MODE scores (p-value = 0.001). CONCLUSION: Quantifying multi-organ injury is important to plan optimal early management and long-term follow-up. Additional use of clinical biomarkers may be useful as surrogate endpoints in future clinical trials and link to multi-organ longer-term developmental follow-up.

Peri-operative myocardial performance in infants with Down syndrome undergoing CHD repair.

BACKGROUND: We aimed to characterise the impact of Down syndrome on myocardial performance and loading conditions in infants with Down syndrome and CHD over the peri-operative period by comparing them with infants matched for cardiac lesion with a normal microarray. METHODS: Left ventricular global longitudinal strain, right ventricular free wall longitudinal strain, left ventricular end-systolic wall stress, and right ventricular systolic pressure were measured in the two groups over the peri-operative period. RESULTS: Fifty-five infants had a diagnosis of Down syndrome and these were compared with 29 control infants. Left ventricular global longitudinal strain decreased in both groups post-operatively with the Down syndrome group demonstrating some recovery pre-discharge (18 ± 3 versus 16 ± 3 %, p = 0.01). Right ventricular longitudinal strain significantly decreased in both groups post-operatively with the control group demonstrating better recovery by hospital discharge (14 ± 4 versus 18 ± 6 %, p < 0.01). End-systolic wall stress was lower and right ventricular systolic pressure was higher in the Down syndrome group throughout the study period (all p < 0.05). Down syndrome was an independent predictor of the duration of ventilation, post-operative use of inotropes, and intensive care stay. Right ventricular longitudinal strain was an independent predictor of duration of intensive care stay. CONCLUSION: This study demonstrates the difference between the two groups in relation to left and right ventricular function, particularly prior to discharge, and outlines the additional impact a diagnosis of Down syndrome has on myocardial performance during the peri-operative period.

A Pilot Randomized Controlled Trial of Early Targeted Patent Ductus Arteriosus Treatment Using a Risk Based Severity Score (The PDA RCT).

OBJECTIVES: To evaluate the feasibility of recruiting preterm infants to a randomized controlled trial of patent ductus arteriosus (PDA) treatment based on a PDA severity score (PDAsc) and to characterize challenges in obtaining consent, compliance with the protocol, and PDA closure rates. STUDY DESIGN: This single-center, randomized control pilot study of 60 infants <29 weeks of gestation with a high PDAsc (≥5.0) at 36-48 hours of age receiving either ibuprofen or placebo intravenously. The study protocol did not allow for additional PDA therapy within the first 2 weeks. We reported the rate of consent, open label treatment, and PDA closure rates. The primary outcome was chronic lung disease or death. RESULTS: We approached 83 families for enrollment with 73 (88%) providing consent; 13 infants had a PDAsc of <5; of the remaining infants, 30 were assigned ibuprofen and 30 received placebo. Eight infants received open label treatment in the first 2 weeks (12%). The overall PDA closure rate after treatment was 57% in the intervention group and 17% in the control group (P < .01). There was no difference in the primary clinical outcome (OR, 0.8; 95% CI, 0.3-2.1). CONCLUSIONS: Using a PDAsc for infant recruitment to a PDA treatment randomized controlled trial is feasible. There is a high rate of consent and relatively low rate of open-label PDA treatment. The overall PDA closure rate in the intervention arm was low placing the emphasis on devising more effective PDA closure strategies in future randomized controlled trials. TRIAL REGISTRATION: ISRCTN (13281214) and European Union Drug Regulating Authorities Clinical Trials Database (2015-004526-33).

A review of the role of extracellular vesicles in neonatal physiology and pathology.

Extracellular vesicles (EVs) are cell-derived membrane-bound particles, extensively investigated across many fields to improve the understanding of pathophysiological processes, as biomarkers of disease and as therapeutic targets for pharmacological intervention. We aim to describe the current knowledge of EVs detected in the body fluids of human neonates, both term and preterm, from birth to 4 weeks of age. To date, EVs have been described in several neonatal body fluids, including cerebrospinal fluid, umbilical cord blood, neonatal blood, tracheal aspirates and urine. These studies demonstrate some important roles of EVs in the neonatal population, particularly in haemostasis. Moreover, some studies have demonstrated the pathophysiological mechanisms and the identification of potential biomarkers of neonatal disease. We must continue to build on this knowledge, evaluating the role of EVs in neonatal pathology, particularly in prematurity and during the perinatal adaption period. Future studies should use larger numbers, robust EV characterisation techniques and always correlate the findings to clinical outcomes. IMPACT: This article summarises the current knowledge of the effect of EVs in neonates. It describes the potential compensatory role of EVs in neonatal haemostasis. It also describes the role of EVs as mediators of pathology and as potential biomarkers of perinatal and neonatal disease.

Cerebral oxygen saturation and autoregulation during hypotension in extremely preterm infants.

BACKGROUND: The impact of the permissive hypotension approach in clinically well infants on regional cerebral oxygen saturation (rScO2) and autoregulatory capacity (CAR) remains unknown. METHODS: Prospective cohort study of blinded rScO2 measurements within a randomized controlled trial of management of hypotension (HIP trial) in extremely preterm infants. rScO2, mean arterial blood pressure, duration of cerebral hypoxia, and transfer function (TF) gain inversely proportional to CAR, were compared between hypotensive infants randomized to receive dopamine or placebo and between hypotensive and non-hypotensive infants, and related to early intraventricular hemorrhage or death. RESULTS: In 89 potentially eligible HIP trial patients with rScO2 measurements, the duration of cerebral hypoxia was significantly higher in 36 hypotensive compared to 53 non-hypotensive infants. In 29/36 hypotensive infants (mean GA 25 weeks, 69% males) receiving the study drug, no significant difference in rScO2 was observed after dopamine (n = 13) compared to placebo (n = 16). Duration of cerebral hypoxia was associated with early intraventricular hemorrhage or death.  Calculated TF gain (n = 49/89) was significantly higher reflecting decreased CAR in 16 hypotensive compared to 33 non-hypotensive infants. CONCLUSIONS: Dopamine had no effect on rScO2 compared to placebo in hypotensive infants. Hypotension and cerebral hypoxia are associated with early intraventricular hemorrhage or death. IMPACT: Treatment of hypotension with dopamine in extremely preterm infants increases mean arterial blood pressure, but does not improve cerebral oxygenation. Hypotensive extremely preterm infants have increased duration of cerebral hypoxia and reduced cerebral autoregulatory capacity compared to non-hypotensive infants. Duration of cerebral hypoxia and hypotension are associated with early intraventricular hemorrhage or death in extremely preterm infants. Since systematic treatment of hypotension may not be associated with better outcomes, the diagnosis of cerebral hypoxia in hypotensive extremely preterm infants might guide treatment.

Cardiac Function and Ventricular Interactions in Persistent Pulmonary Hypertension of the Newborn.

OBJECTIVES: The aim of this study was to use a comprehensive imaging protocol to identify echocardiographic correlations of right and left ventricular size, function, and hemodynamics in neonates with persistent pulmonary hypertension of newborn and describe their relationship with key clinical variables. DESIGN: Retrospective case-control echocardiography-based study of persistent pulmonary hypertension of newborn. SETTING: A tertiary neonatal ICU in Canada. PATIENTS: Forty-nine neonates (gestational age ≥ 35 wk old) diagnosed with persistent pulmonary hypertension of newborn within first 3 days after birth and 50 age-matched controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The echocardiographic measurements comprised of right ventricular and left ventricular functional markers, including tricuspid annular plane systolic excursion, fractional area change, tissue Doppler imaging, and deformation imaging. Sample size was based on detecting an intergroup difference of 10% in tricuspid annular plane systolic excursion, which was considered the primary outcome. Linear correlations between the right and left ventricular indices, as well as their association with the outcome of death or extracorporeal membrane oxygenation were evaluated. Persistent pulmonary hypertension of newborn was associated with lower tricuspid annular plane systolic excursion (6.81 ± 1.92 vs 9.25 ± 1.30 mm), right-ventricular global longitudinal strain (16.9% ± 5.4% vs -21.6% ± 4.6%); left ventricular ejection fraction (49% ± 7% vs 55% ± 6%), left ventricular global longitudinal strain (-16.7% ± 3.3% vs -21.4% ± 2.0%) (all p < 0.01). Right and left ventricular diastolic and global function was also lower in persistent pulmonary hypertension of newborn, with more pronounced changes seen for the right ventricle. Moderate-to-strong linear correlations were observed between the right and left ventricular functional markers, with right ventricular global longitudinal strain and left ventricular global longitudinal strain being the strongest (r = 0.8). Within persistent pulmonary hypertension of newborn group, hypoxic ischemic encephalopathy was associated with lower right and left ventricular systolic and right ventricular diastolic performance. Tricuspid annular plane systolic excursion (p =0.08) and left ventricular systolic velocity (p = 0.09) tended to be lower in patients who subsequently died/needed extracorporeal membrane oxygenation. CONCLUSIONS: Persistent pulmonary hypertension of newborn is characterized by global cardiac dysfunction, involving both the right and left ventricles, with significant interventricular functional correlation. Cardiac dysfunction early in disease course may identify patients at highest risk of adverse outcome.

Preventing disease in the 21st century: early breast milk exposure and later cardiovascular health in premature infants.

Cardiovascular health of premature infants reaching early adulthood is an area of ongoing research. There is emerging evidence delineating the challenges faced by those individuals. Young adults born premature demonstrate a unique cardiac phenotype characterized by reduced biventricular volume, relatively lower systolic and diastolic function, and a disproportionate increase in muscle mass. This may clinically manifest by an increased risk of cardiovascular incidents, hypertension, and reduced exercise tolerance. Those consequences appear to result from early postnatal cardiac remodeling due to premature birth and associated co-morbidities. Recent evidence suggests that early exposure to breast milk slows down or even arrests those pathophysiological changes, thereby mitigating the long-term adverse effects of premature birth on cardiovascular health. In this review article, we discuss the role of breast milk in preventing early adulthood cardiovascular disease in infants born premature. We explore the emerging evidence and examine the possible mechanistic pathways mediating this phenomenon. Furthermore, we aim to demonstrate the vital role of early breast milk exposure in preventing cardiovascular disease in preterm infants.