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We aimed to review the physiology and evidence behind cardiorespiratory interactions during the transitional circulation of extremely preterm infants with fragile physiology and to propose a framework for future research. Cord clamping strategies have a great impact on initial haemodynamic changes, and appropriate transition can be facilitated by establishing spontaneous ventilation before cord clamping. Mechanical ventilation modifies preterm transitional haemodynamics, with positive pressure ventilation affecting the right and left heart loading conditions. Pulmonary vascular resistances can be minimized by ventilating with optimal lung volumes at functional residual capacity, and other pulmonary vasodilator treatments such as inhaled nitric oxide can be used to improve ventilation/perfusion mismatch. Different cardiovascular drugs can be used to provide support during transition in this population, and it is important to understand both their cardiovascular and respiratory effects, in order to provide adequate support to vulnerable preterm infants and improve outcomes. Current available non-invasive bedside tools, such as near-infrared spectroscopy, targeted neonatal echocardiography, or lung ultrasound offer the opportunity to precisely monitor cardiorespiratory interactions in preterm infants. More research is needed in this field using precision medicine to strengthen the benefits and avoid the harms associated to early neonatal interventions. IMPACT: In extremely preterm infants, haemodynamic and respiratory transitions are deeply interconnected, and their changes have a key impact in the establishment of lung aireation and postnatal circulation. We describe how mechanical ventilation modifies heart loading conditions and pulmonary vascular resistances in preterm patients, and how hemodynamic interventions such as cord clamping strategies or cardiovascular drugs affect the infant respiratory status. Current available non-invasive bedside tools can help monitor cardiorespiratory interactions in preterm infants. We highlight the areas of research in which precision medicine can help strengthen the benefits and avoid the harms associated to early neonatal interventions.

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Non-invasive cardiac output monitoring, via electrical biosensing technology (EBT), provides continuous, multi-parameter hemodynamic variable monitoring which may allow for timely identification of hemodynamic instability in some neonates, providing an opportunity for early intervention that may improve neonatal outcomes. EBT encompasses thoracic (TEBT) and whole body (WBEBT) methods. Despite the lack of relative accuracy of these technologies, as compared to transthoracic echocardiography, the use of these technologies in neonatology, both in the research and clinical arena, have increased dramatically over the last 30 years. The European Society of Pediatric Research Special Interest Group in Non-Invasive Cardiac Output Monitoring, a group of experienced neonatologists in the field of EBT, deemed it appropriate to provide recommendations for the use of TEBT and WBEBT in the field of neonatology. Although TEBT is not an accurate determinant of cardiac output or stroke volume, it may be useful for monitoring longitudinal changes of hemodynamic parameters. Few recommendations can be made for the use of TEBT in common neonatal clinical conditions. It is recommended not to use WBEBT to monitor cardiac output. The differences in technologies, study methodologies and data reporting should be addressed in ongoing research prior to introducing EBT into routine practice. IMPACT STATEMENT: TEBT is not recommended as an accurate determinant of cardiac output (CO) (or stroke volume (SV)). TEBT may be useful for monitoring longitudinal changes from baseline of hemodynamic parameters on an individual patient basis. TEBT-derived thoracic fluid content (TFC) longitudinal changes from baseline may be useful in monitoring progress in respiratory disorders and circulatory conditions affecting intrathoracic fluid volume. Currently there is insufficient evidence to make any recommendations regarding the use of WBEBT for CO monitoring in neonates. Further research is required in all areas prior to the implementation of these monitors into routine clinical practice.

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Neonatal ventriculomegaly often, but not always, follows intraventricular haemorrhage in infants born preterm. Serial cranial ultrasonography (CUS) is a very useful tool to evaluate the mechanism behind ventricular dilatation, to differentiate several types of cerebrospinal fluid retention, and to guide treatment. This review examines neonatal ventriculomegaly and its definition, pathophysiology, treatment, and prognosis from the perspective of CUS assessment. It also outlines the consensus statements formulated by the EurUS.Brain group, which are based on rounds of expert opinions on neonatal ventriculomegaly management, detailing the need and timing of ventricular access device placement, in the context of posthaemorrhagic ventricular dilation. The pathophysiology of neonatal ventriculomegaly is more complex than previously considered. CUS is a valuable, non-invasive tool to determine pathophysiology, intervention thresholds, and prognosis in neonates with ventriculomegaly. Given new insights into the existence of glymphatics and water circulation in the cerebrum, further research in that area may bring new treatment options.

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OBJECTIVE: To determine whether early echocardiography screening of low systemic blood flow reduces intraventricular hemorrhage in preterm infants. STUDY DESIGN: Prospective multicenter study in preterm infants below 33 weeks of gestational age at nine neonatal units. Five units performed early echocardiography screening for low systemic blood flow and guided clinical management (exposure group) and 4 units did not (control group). Our main outcome was ≥grade II intraventricular hemorrhage or death within the first 7 days of life. The main analysis used the inverse probability of treatment weighting. RESULTS: Three hundred and thirty-two preterm infants (131 in the exposure group and 201 in the control group) were included. Exposure to early echocardiography screening was associated with a significant reduction in ≥grade II intraventricular hemorrhage or early death [odds ratio 0.285 (95% CI: 0.133-0.611); p = 0.001]. CONCLUSIONS: Early echocardiography screening for low systemic blood flow may reduce the incidence of intraventricular hemorrhage in preterm infants.

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BACKGROUND: Cardiovascular support (CVS) treatment failure (TF) is associated with a poor prognosis in preterm infants. METHODS: Medical charts of infants with a birth weight <1500 g who received either dopamine (Dp) or dobutamine (Db), were reviewed. Treatment response (TR) occurred if blood pressure increased >3rd centile for gestational age or superior vena cava flow was maintained >55 ml/kg/min, with decreased lactate or less negative base excess, without additional CVS. A predictive model of Dp and Db on TR was designed and the impact of TR on survival was analyzed. RESULTS: Sixty-six infants (median gestational age 27.3 weeks, median birth weight 864 g) received Dp (n = 44) or Db (n = 22). TR occurred in 59% of the cases treated with Dp and 31% with Db, p = 0.04. Machine learning identified a model that correctly labeled Db response in 90% of the cases and Dp response in 61.4%. Sixteen infants died (9% of the TR group, 39% of the TF group; p = 0.004). Brain or gut morbidity-free survival was observed in 52% vs 30% in the TR and TF groups, respectively (p = 0.08). CONCLUSIONS: New predictive models can anticipate Db but not Dp effectiveness in preterm infants. These algorithms may help the clinicians in the decision-making process. IMPACT: Failure of cardiovascular support treatment increases the risk of mortality in very low birth weight infants. A predictive model built with machine learning techniques can help anticipate treatment response to dobutamine with high accuracy. Predictive models based on artificial intelligence may guide the clinicians in the decision-making process.

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OBJECTIVE: To systematically assess white matter injury (WMI) in preterm infants with posthemorrhagic ventricular dilatation (PHVD) using a high-threshold intervention strategy. STUDY DESIGN: This retrospective analysis included 85 preterm infants (≤34 weeks of gestation) with grade 2-3 germinal matrix-intraventricular hemorrhage. Cranial ultrasound (cUS) scans were assessed for WMI and ventricular width and shape. Forty-eight infants developed PHVD, 21 of whom (intervention group) underwent cerebrospinal fluid drainage according to a predefined threshold (ventricular index ≥p97+4 mm or anterior horn width >10 mm, and the presence of frontal horn ballooning). The other 27 infants underwent a conservative approach (non-intervention group). The two PHVD groups were compared regarding ventricular width at two stages: the worst cUS for the non-intervention group (scans showing the largest ventricular measurements) versus pre-intervention cUS in the intervention group, and at term equivalent age. WMI was classified as normal/mild, moderate and severe. RESULTS: The intervention group showed significantly larger ventricular index, anterior horn width and thalamo-occipital diameter than the non-intervention group at the two timepoints. Moderate and severe WMI were more frequent in the infants with PHVD (p<0.001), regardless of management (intervention or conservative management). There was a linear relationship between the severity of PHVD and WMI (p<0.001). CONCLUSIONS: Preterm infants with PHVD who undergo a high-threshold intervention strategy associate an increased risk of WMI.

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Background: Patent ductus arteriosus (PDA) treatment remains controversial. Modeling on the predictive capacity of early spontaneous PDA closure would help in decision-making. Aim: To design a predictive model of early spontaneous PDA closure. Methods: As part of a trial to assess efficacy and safety of two ibuprofen treatment schemes for PDA, infants below 29 weeks' gestation were scanned between 18 and 72 h of birth, and serially if indicated. PDA treatment was decided based on echocardiography signs of lung overflow or systemic hypoperfusion and clinical criteria. A PDA score that included the echocardiographic parameters significantly associated with treatment prescription was retrospectively applied. Perinatal variables and screening score were included in a backwards elimination model to predict early spontaneous closure. Results: Among 87 eligible infants (27 weeks' gestation; age at screening 45 h), 21 received ibuprofen at 69 h of life [screening score = 7 (IQR = 5-8.5); score at treatment = 9 (IQR = 8-9)], while 42 infants had conservative management, [screening score = 1 (IQR = 0-4)]. Twenty four infants were excluded (ibuprofen contraindication, declined consent or incomplete echocardiography). Screening score showed an AUC = 0.93 to predict early spontaneous PDA closure, [cut-off value = 4.5 (sensitivity = 0.90, specificity = 0.86)]. The predictive model for early spontaneous PDA closure followed the equation: Log (p/1-p) = -28.41 + 1.23* gestational age -0.87* PDA screening score. Conclusions: A predictive model of early spontaneous PDA closure that includes gestational age and the screening PDA score is proposed to help clinicians in the decision- making for PDA treatment. In addition, this model could be used in future intervention trials aimed to prevent PDA related morbidities to improve the eligibility criteria.

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AIM: Although circulatory impairment during the transitional circulation associates morbidity and mortality, its treatment remains controversial. In a pilot trial on circulatory impairment defined as low superior vena cava (SVC) flow, dobutamine (Db) versus placebo (PL) showed a trend towards improved short-term outcomes. The purpose of this study was to report on the long-term outcome of the infants who were observed for SVC flow patterns. METHODS: Among the 126 infants <31 weeks of gestation prospectively scanned from birth, 28 presented low SVC flow within the first 24 h after birth and received Db (n = 16) or PL (n = 12). Follow-up of survivors included motor assessment and Bayley Scales II or III at 2 years, and the Reynolds Intellectual Assessment Scale at 6 years. Neurodevelopmental impairment (NDI) was defined as: cerebral palsy (Gross Motor Function Classification System ≥ level 2), or a cognitive function score < -2 standard deviations; or moderate or severe hearing or visual impairment. Db group, PL group and normal-flow group were compared. RESULTS: Eighteen infants died (Db: 5; PL: 2; normal flow group: 11, P = 0.1). Follow-up in survivors was accomplished in 80% and 55% of the cohort at 2 years and 6 years, respectively. No significant difference in the combined outcome (mortality or NDI) was found between the groups (42% Db, 36% PL, 30% normal flow group). CONCLUSIONS: This exploratory analysis did not show any differences in the long-term outcome of infants according to SVC flow patterns or its treatment early after birth.

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OBJECTIVE: Patent ductus arteriosus (PDA) approach remains controversial. We aim to evaluate whether echocardiography-guided (EchoG) PDA closure (to reduce drug exposure) and 24-h continuous ibuprofen infusion (24 h-IB) (to reduce peak concentration), compared with EchoG PDA closure plus conventional bolus (bolus-IB), reduces severe bowel adverse event rate in preterm infants with hemodynamically significant (hs) PDA. STUDY DESIGN: The study design is a multicenter, blinded, randomized controlled trial. Infants with <28 weeks of gestation underwent routine echocardiographic assessment (18-72 h of birth); infants with 28-33 weeks were screened only in cases where PDA was clinically suspected. HsPDA was considered if ductal diameter >1.5 mm and indicators of pulmonary overflow, systemic hypoperfusion, or both were present. Pharmacodynamic effect of CYP450 genotypes was also analyzed. RESULTS: One hundred forty-six infants [median gestational age 26 (25-28) weeks; median birth weight 881 (704-1,100) g] were randomized to 24 h-IB (n = 70) or bolus-IB (n = 76) study group at 86 (58-140) h from birth. Groups were comparable regarding perinatal and neonatal clinical data, but higher prevalence of male sex in the bolus-IB group was found. Neither severe bowel adverse event rate [10% (24 h-IB) and 2.6% (bolus-IB), p = 0.1] nor ductal closure rate was different between the study groups. Postnatal age and peripheral SaO2 at treatment start and pulmonary hemorrhage were associated with severe bowel events, independent of treatment group allocation. CYP2C8 genetic polymorphisms were associated with ibuprofen efficacy (p = 0.03). CONCLUSIONS: Ibuprofen intravenous continuous infusion compared with bolus infusion in preterm infants with hsPDA shows similar rates of success and does not reduce the prevalence of severe bowel events.

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BACKGROUND: Dobutamine is particularly suited to treatment of haemodynamic insufficiency caused by increased peripheral vascular resistance and myocardial dysfunction in the preterm infant. Knowledge of the elimination half-life is essential to estimate the steady state when its efficacy/safety can be evaluated. METHODS: Analysis of pharmacokinetic data in ten preterm newborns treated with a new neonatal formulation of dobutamine (IMP) after screening for haemodynamic insufficiency within the first 72 h from birth. Blood samples were withdrawn at the end of IMP infusion and at a random time after the end of infusion (5 min, 15 min, 45 min, 2 h and 6 h). IMP concentration in each sample was measured by ultra-high performance liquid chromatography with electrochemical detection. RESULTS: Median duration of IMP infusion was 37.7 h (IQR 21.2). Calculated IMP half-life ranged between 3.06 and 36.1 min (median 10.6 min), leading to a time to reach the steady-state concentration between 15 min and >2 h. Adverse events were not related to IMP. CONCLUSIONS: The wide variability in dobutamine metabolism in preterm infants requires awareness about the risk of under- or overtreatment. A delay of up to 3 h might be required before drawing blood samples to evaluate the effective dose. IMPACT: Small trials suggest dobutamine as the optimal drug in the preterm infant with haemodynamic insufficiency after birth. Age-related differences in drug pharmacokinetics may result in suboptimal treatments. The lack of formal studies in preterms results in inadequate data on efficacy and safety. This study provides data on the variability of the elimination half-life of dobutamine in the very preterm infant during transitional circulation. There is a wide variation in the time to reach the plasma concentration corresponding to steady state, the moment when its efficacy/safety can be reliably evaluated. This information is crucial for planning future trials on cardiovascular support.

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Germinal matrix-intraventricular haemorrhage (GMH-IVH), periventricular haemorrhagic infarction (PHI) and its complication, post-haemorrhagic ventricular dilatation (PHVD), are still common neonatal morbidities in preterm infants that are highly associated with adverse neurodevelopmental outcome. Typical cranial ultrasound (CUS) findings of GMH-IVH, PHI and PHVD, their anatomical substrates and underlying mechanisms are discussed in this paper. Furthermore, we propose a detailed descriptive classification of GMH-IVH and PHI that may improve quality of CUS reporting and prediction of outcome in infants suffering from GMH-IVH/PHI.

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La ecografía a pie de cama (EPC) se ha convertido en los últimos años en una herramienta imprescindible para la práctica clínica. La EPC debe entenderse como una extensión de la exploración física habitual que, sin sustituirla, la complementa y la enriquece. La EPC permite al clínico responder preguntas concretas sobre el diagnóstico, entender mejor la fisiopatología, orientar el tratamiento o realizar procedimientos invasivos con mayor seguridad. A pesar de su integración en muchos centros y en las diferentes subespecialidades pediátricas, no disponemos de recomendaciones específicas que establezcan los objetivos formativos en las distintas áreas de capacitación, la metodología de entrenamiento o la certificación de competencias en pediatría. Estos elementos son imprescindibles para que la EPC pueda implementarse en la práctica diaria con garantías de eficiencia y seguridad. Este artículo aborda las principales aplicaciones de la EPC en pediatría mediante una revisión no sistemática por parte de expertos en diferentes áreas de la práctica clínica en España. Además, se discute acerca de la falta de planes formativos a nivel estatal, contando con la aportación de la experiencia de Estados Unidos. En vista de la situación actual de la EPC, en nuestra opinión es urgente que se establezcan recomendaciones basadas en la evidencia para el entrenamiento en EPC que sirvan como base para el desarrollo de planes formativos y la integración de la EPC en el programa formativo de la especialidad

Point-of-care ultrasound (POCUS) has become an essential tool for clinical practice in recent years. It should be considered as an extension of the standard physical examination, which complements and enriches it without substituting it. POCUS enables the physician to answer specific clinical questions about the diagnosis, to understand better the pathophysiological context, to orientate the treatment, and to perform invasive procedures more safely. Despite its current use in many centres, and in most paediatric sub-specialties, there are currently no specific recommendations addressing educational aims in the different training areas, as well as methodology practice and the certification process in paediatrics. These ingredients are essential for POCUS implementation in daily practice, with a quality guarantee in terms of efficiency and safety. Several POCUS experts in different paediatric medicine environments performed a non-systematic review addressing the main paediatric POCUS applications in paediatrics. The lack of educational programs in POCUS in Spain is also discussed, and the experience in the United States of America in this topic is provided. Considering the current situation of POCUS in paediatrics, we strongly believe that it is urgent to establish evidence-based recommendations for POCUS training that should be the base to develop educational programs and to include POCUS in the paediatric residency training

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Point-of-care ultrasound (POCUS) has become an essential tool for clinical practice in recent years. It should be considered as an extension of the standard physical examination, which complements and enriches it without substituting it. POCUS enables the physician to answer specific clinical questions about the diagnosis, to understand better the pathophysiological context, to orientate the treatment, and to perform invasive procedures more safely. Despite its current use in many centres, and in most paediatric sub-specialties, there are currently no specific recommendations addressing educational aims in the different training areas, as well as methodology practice and the certification process in paediatrics. These ingredients are essential for POCUS implementation in daily practice, with a quality guarantee in terms of efficiency and safety. Several POCUS experts in different paediatric medicine environments performed a non-systematic review addressing the main paediatric POCUS applications in paediatrics. The lack of educational programs in POCUS in Spain is also discussed, and the experience in the United States of America in this topic is provided. Considering the current situation of POCUS in paediatrics, we strongly believe that it is urgent to establish evidence-based recommendations for POCUS training that should be the base to develop educational programs and to include POCUS in the paediatric residency training.

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Objectives: The definition of circulatory impairment in the premature infant is controversial. Current research suggests overdiagnosis and overtreatment. We aimed to analyse which biomarkers move clinicians to initiate cardiovascular treatment (CVT). The prognostic capacity for adverse outcome (death and/or moderate-severe brain damage by cranial ultrasound at term equivalent) of these biomarkers was evaluated. Study Design: Retrospective data analysis from preterm infants enrolled in a placebo-controlled trial on dobutamine for low superior vena cava (SVC) flow, who showed normal SVC flow within the first 24 h (not randomized). Five positive biomarkers were considered: MABP < gestational age (GA)-1 mmHg; MABP < GA-5 mmHg; lactate > 4 mmol/L; BE < -9 mmol/L; SVC flow <51 ml/kg/min. Results: Ninety eight infants formed the study cohort. Thirty six received CVT (2-95 h). Logistic regression models adjusted for gestational age showed a positive association between CVT and the risk of death or moderate-severe abnormal cranial ultrasound at term equivalent [(OR 5.2, 95%CI: 1.8-15.1) p = 0.002]. MABP < GA-1 mmHg and lactate > 4 mmol/L were the most prevalent biomarkers at start of treatment. Low BE, high serum lactate and low SVC flow at first echocardiography showed a trend toward being associated with adverse outcome, although not statistically significant. Conclusions: Low blood pressure and high lactate are the most prevalent biomarkers used for CVT prescription. Lactic acidosis and low SVC flow early after birth showed a trend toward being associated with adverse outcome. These findings support using a combination of biomarkers for inclusion in a placebo-controlled trial on CVT during transitional circulation.

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BACKGROUND: Post-ligation cardiac syndrome (PLCS) is a common complication of patent ductus arteriosus (PDA) surgical closure in low birth weight infants. It has been associated with mortality, but there is a lack of information about the neurodevelopmental outcome of the survivors. We aimed to explore the prevalence of PLCS and to assess whether this clinical condition is a risk factor for adverse outcome, (moderate or severe neurodevelopmental disabilities). METHODS: We retrospectively reviewed the medical charts of all the infants < 30 weeks of gestation who underwent ductus arteriosus ligation at our unit between 2005 and 2009. RESULTS: During the study period, 39 preterm infants [mean gestational age 26.4 (2) weeks] underwent surgical closure of the PDA at a mean postnatal age of 25.3 (2.3) days. Twenty six percent of the study population developed PLCS. Five infants died and the follow-up was accomplished in 24 infants (70% of the survivors) at a mean age of 5.3 (1.5) years (range 2-9 years). Neurodevelopmental impairment was observed in 6 in the PLCS group (75%) and in 6 infants in the no PLCS group (37%), p = 0.08]. Multiple regression analyses showed that the best fitting model for predicting adverse outcome included PLCS and low birth weight, p = 0.018. CONCLUSION: Preterm infants undergoing surgical closure of PDA who fulfill the criteria of PLCS according to this study seem to have a tendency toward higher risk of long-term neurodevelopmental impairment. Prospective clinical trials reporting long-term follow-up data should be designed to confirm the hypotheses generated in this pilot study.

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BACKGROUND: Circulatory failure in preterm and term newborn infants is commonly treated with inotropes or vasoactive medications. In this structured literature review, the available data on pharmacodynamic effects of the inotropes adrenaline, dobutamine, dopamine, levosimendan, milrinone, noradrenaline, and the vasoactive drugs vasopressin and hydrocortisone are presented. METHODS: Structured searches were conducted to identify relevant articles according to pre-defined inclusion criteria which were human clinical trials published after 2000. RESULTS: Out of 101 identified eligible studies only 22 studies met the criteria for evidence based practice guidelines level I to IV. The most prevalent pharmacodynamic effects were increase in blood pressure and/or heart rate, which were also the most frequently studied circulatory parameters. CONCLUSION: This review demonstrates the need for further systematic studies on all reviewed drugs with incorporation of novel non-invasive biomarkers in this vulnerable patient group, for more timely and appropriate treatment for clinical efficacy.

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BACKGROUND: Cerebellar size appears to be correlated with the long-term outcome of preterm infants. Two-dimensional cranial ultrasonography (2D-cUS) is the first-line, routine tool to characterize newborn cerebral structures. Information regarding the accuracy of 2D-cUS for assessing cerebellar size is scarce. OBJECTIVES: To assess the reliability of cerebellar size using 2D-cUS. METHODS: Fifty infants were prospectively scanned for a variety of clinical indications. The scans were stored and then independently analyzed offline by two observers. The transverse cerebellar diameter coronally from the anterior and mastoid fontanels (TCD-AF and TCD-MF, respectively); the midsagittal cerebellar vermis height and the anterior-posterior diameter from the AF; and the width and height of the fourth ventricle coronally from the MF view were measured. Interobserver variability was assessed using the intraclass correlation (ICC) with 95% confidence interval (CI) for each of the paired measures. RESULTS: A total 294 images were included in the analysis. The interobserver ICCs were TCD-AF = 0.85 (0.76-0.91), TCD-MF = 0.9 (0.83-0.94), vermis height = 0.79 (0.66-0.88), anterior-posterior vermis diameter = 0.71 (0.5-0.84), width of the fourth ventricle = 0.72 (0.33-0.9), height of the fourth ventricle = 0.86 (0.7-0.92). The ICC for the TCD comparing the AF and the MF approach was ≥0.9 for both observers. CONCLUSIONS: The reliability of the offline 2D-cUS cerebellar size assessments is good, and TCD-MF is the most consistent measure. Further studies should address the predictive value for the neurodevelopmental outcome of serial cerebellar size assessments by 2D-cUS for preterm infants.

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