Prevention of Chronic Morbidities in Extremely Premature Newborns with LISA-nCPAP Respiratory Therapy and Adjuvant Perinatal Strategies.

Less invasive surfactant administration techniques, together with nasal continuous airway pressure (LISA-nCPAP) ventilation, an emerging noninvasive ventilation (NIV) technique in neonatology, are gaining more significance, even in extremely premature newborns (ELBW), under 27 weeks of gestational age. In this review, studies on LISA-nCPAP are compiled with an emphasis on short- and long-term morbidities associated with prematurity. Several perinatal preventative and therapeutic investigations are also discussed in order to start integrated therapies as numerous organ-saving techniques in addition to lung-protective ventilations. Two thirds of immature newborns can start their lives on NIV, and one third of them never need mechanical ventilation. With adjuvant intervention, these ratios are expected to be increased, resulting in better outcomes. Optimized cardiopulmonary transition, especially physiologic cord clamping, could have an additively beneficial effect on patient outcomes gained from NIV. Organ development and angiogenesis are strictly linked not only in the immature lung and retina, but also possibly in the kidney, and optimized interventions using angiogenic growth factors could lead to better morbidity-free survival. Corticosteroids, caffeine, insulin, thyroid hormones, antioxidants, N-acetylcysteine, and, moreover, the immunomodulatory components of mother's milk are also discussed as adjuvant treatments, since immature newborns deserve more complex neonatal interventions.

Perinatal stroke: management guideline / Perinatalis stroke: Vizsgálati irányelv

A perinatalis stroke egy heterogen neurologiai szindroma, mely agyi erserules kovetkezteben alakul ki, es hosszu tavon altalaban kronikus neurologiai kimenetellel jar. Az akut stroke-ok koze a perinatalis arterias ischaemias stroke, a sinusthrombosis es a perinatalis verzeses stroke tartozik. A kes??bb, altalaban 4-8 honapos kor kozott motoros aszimmetriat okozo korkepeket feltetelezetten perinatalis eredet?? stroke-nak nevezzuk. A magneses rezonancias perinatalis stroke-ot. Az ujabb adatok szerint a perinatalis stroke incidenciaja 1 korul van 1100 elveszuletesb??l (1/1100). Bar a stroke-os ujszulottek 40%-a kes??bb tunetmentesen fejl??dik, a tobbiek hosszu tavu neurologiai kimenetele koros, es a karosodas spektrumahoz cerebralparesis, epilepszia, kognitiv karosodas, magatartaszavar, beszedzavar es/vagy valamilyen erzekszervi karosodas tartozik. Az utobbi id??ben tobb tanulmany vizsgalta a rizikotenyez??k, az MR-kepek es a kimenetel osszefuggeset. A jelen osszefoglalo kozlemenyben a perinatalis stroke perinatalis stroke vizsgalatanak meneter??l es terapiajarol iranyelvet keszitettunk.

Long-term neurodevelopmental outcome of neonates born at term with perinatal haemorrhagic stroke: A population-based study.

AIM: To assess the long-term neurodevelopmental outcome of neonates born at term diagnosed with perinatal haemorrhagic stroke (PHS) and investigate the associations among brain territorial involvement, clinical risk factors, and neurodevelopmental outcomes. METHOD: We conducted a population-based study enrolling 55 neonates born at term with PHS confirmed by magnetic resonance imaging born between 2007 and 2017. Long-term neurodevelopmental outcome was assessed using the Bayley Scales of Infant Development, Second Edition, the Brunet-Lézine test, and the Stanford-Binet Intelligence Scales, Fifth Edition. RESULTS: Follow-up was available in 50 (91%) of the infants, at a median age of 60 months (interquartile range 35-88). Forty per cent of the infants developed according to population norms, and developmental disabilities were diagnosed less frequently among neonates with frontal lobe PHS. In a multivariable model, parietal lobe PHS increased the risk for cerebral palsy (odds ratio [OR] 6.7; 95% confidence interval [CI] 1.1-41.4) and cognitive impairment (OR: 23.6; 95% CI: 2.9-194.9), while the involvement of the thalamus and/or basal ganglia was associated with epilepsy (OR: 7.0; 95% CI: 1.3-37.7). Seizures on admission were associated with epilepsy (OR: 10.8; 95% CI: 1.8-64.3). Patients with PHS affecting multiple lobes had poor prognosis. INTERPRETATION: Parietal lobe haemorrhage, the involvement of the thalamus/basal ganglia, PHS affecting multiple lobes, and seizures were independent predictors of chronic neurodevelopmental sequelae, suggesting that the stroke territorial involvement and clinical risk factors influence the outcome of PHS.

The role of brain territorial involvement and infection/inflammation in the long-term outcome of neonates with arterial ischemic stroke: A population-based cohort study.

BACKGROUND: Neonatal arterial ischemic stroke (NAIS) carries the risk of significant long-term neurodevelopmental burden on survivors. AIMS: To assess the long-term neurodevelopmental outcome of term neonates diagnosed with NAIS and investigate the associations among brain territorial involvement on MRI, clinical risk factors and neurodevelopmental outcomes. STUDY DESIGN: Population-based cohort study. SUBJECTS: Seventy-nine term neonates with NAIS confirmed by MRI born between 2007 and 2017. OUTCOME MEASURES: Long-term neurodevelopmental outcome assessed using the Bayley Scales of Infant Development-II, the Brunet-Lézine test and the Binet Intelligence scales-V. RESULTS: Follow-up was available in 70 (89%) of the subjects enrolled, at a median age of 60 months [IQR: 35-84]. Normal neurodevelopmental outcome was found in 43% of the patients. In a multivariable model, infants with main MCA stroke had an increased risk for overall adverse outcome (OR: 9.1, 95% CI: 1.7-48.0) and a particularly high risk for cerebral palsy (OR: 55.9, 95% CI: 7.8-399.2). The involvement of the corticospinal tract without extensive stroke also increased the risk for cerebral palsy/fine motor impairment (OR: 13.5, 95% CI: 2.4-76.3). Multiple strokes were associated with epilepsy (OR: 9.5, 95% CI: 1.0-88.9) and behavioral problems (OR: 4.4, 95% CI: 1.1-17.5) and inflammation/infection was associated with cerebral palsy (OR: 9.8, 95% CI: 1.4-66.9), cognitive impairment (OR: 9.2, 95% CI: 1.8-47.8) and epilepsy (OR: 10.3, 95% CI: 1.6-67.9). CONCLUSIONS: Main MCA stroke, involvement of the corticospinal tract, multiple strokes and inflammation/infection were independent predictors of adverse outcome, suggesting that the interplay of stroke territorial involvement and clinical risk factors influence the outcome of NAIS.

Development and validation of an automated assessment tool of echocardiography skills acquired on a neonatal simulator.

INTRODUCTION: Simulators are increasingly used for training in echocardiography. However, there is no objective method to assess the skills acquired. Our objective was to develop and test an automated method to assess echocardiography skills. METHODS: To automate the image quality evaluation, we expanded our previously developed neonatal echocardiography simulator to enable recording of images of the 26 standard cuts and process the image quality. We then compared the automated and visual methods in scoring image quality of the echocardiograms obtained by 22 trainees. RESULTS: Each echocardiographic image representing a slice of a three-dimensional volume possesses 3 axes (X, Y, and Z) that correspond to the roll, pitch, and yaw angles of the transducer, respectively. Therefore, if the placement and orientation of the transducer are correct, the acquired image represents the appropriate cardiac window with the desired orientation in all 3 axes. The automated system gives a score of 0 if the transducer is not in the appropriate cardiac window. A score of 1, 2, or 3 is given if the image falls within the range of one, two, or three angles, respectively. There was no difference in the image quality score between automated and visual assessment methods (46.0 ± 13.0 vs 45.1 ± 14.4, P = .19). The two methods had excellent correlation (r = .95). The bias and precision were 0.9 and 8.8, respectively. CONCLUSIONS: The automated method is comparable to visual method for assessment of image quality. The automated process allows for instantaneous feedback and has the potential to standardize assessment of echocardiography skills of trainees.

Virtual Neonatal Echocardiographic Training System (VNETS): An Echocardiographic Simulator for Training Basic Transthoracic Echocardiography Skills in Neonates and Infants.

There is a great need for training in pediatric echocardiography. In addition to physicians being trained in pediatric cardiology and echocardiography technologists, neonatologist, pediatric intensivists, and other health care professionals may be interested in such training. Since, there is limited opportunity of training on live patients, echocardiographic simulators may be of help. No simulator with complete range of echocardiographic modalities is available for neonates and infants. The aim of this project was to develop a mannequin-based echocardiographic simulator capable of simulating full range of pediatric 2D, color flow Doppler, spectral Doppler, and M-mode echocardiograms. A mannequin, a laptop computer, a magnetic tracking device, and a six-degree freedom (6DOF) sensor incorporated in a dummy transducer serve as the hardware platform of the simulator. We obtained six to seven 4D echocardiographic datasets in DICOM format through five acoustic windows from each infant along with a complete set of 2D video clips of color flow, Doppler, and M-mode. The 4D datasets are sliced into 3D slices using the visualization toolkit and are displayed as 2D echocardiograms through the information obtained by the 6DOF sensor. The coordinates from specific 3D slices triggers display of video clips of color flow, M-mode, and Doppler echocardiogram. Software written in C++ programming language controls the basic function of the program. The main simulator screen displays the full range of 2D echocardiograms including color flow Doppler, spectral Doppler, and M-mode from each acoustic window, whereas the side screen display the position and motion of the cutting planes through a 3D heart model. The system includes a software module to perform hemodynamic measurements from specific video clips images. Our hybrid, mannequin-based pediatric echocardiography simulator provides full range of pediatric echocardiography training experience. This simulator may help training in pediatric echocardiography for which there is a growing demand in clinical medicine.

Hemodynamic Changes During Rewarming Phase of Whole-Body Hypothermia Therapy in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To delineate the systemic and cerebral hemodynamic response to incremental increases in core temperature during the rewarming phase of therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Continuous hemodynamic data, including heart rate (HR), mean arterial blood pressure (MBP), cardiac output by electrical velocimetry (COEV), arterial oxygen saturation, and renal (RrSO2) and cerebral (CrSO2) regional tissue oxygen saturation, were collected from 4 hours before the start of rewarming to 1 hour after the completion of rewarming. Serial echocardiography and transcranial Doppler were performed at 3 hours and 1 hour before the start of rewarming (T-3 and T-1; "baseline") and at 2, 4, and 7 hours after the start of rewarming (T+2, T+4, and T+7; "rewarming") to determine Cardiac output by echocardiography (COecho), stroke volume, fractional shortening, and middle cerebral artery (MCA) flow velocity indices. Repeated-measures analysis of variance was used for statistical analysis. RESULTS: Twenty infants with HIE were enrolled (mean gestational age, 38.8 ± 2 weeks; mean birth weight, 3346 ± 695 g). During rewarming, HR, COecho, and COEV increased from baseline to T+7, and MBP decreased. Despite an increase in fractional shortening, stroke volume remained unchanged. RrSO2 increased, and renal fractional oxygen extraction (FOE) decreased. MCA peak systolic flow velocity increased. There were no changes in CrSO2 or cerebral FOE. CONCLUSIONS: In neonates with HIE, CO significantly increases throughout rewarming. This is due to an increase in HR rather than stroke volume and is associated with an increase in renal blood flow. The lack of change in cerebral tissue oxygen saturation and extraction, in conjunction with an increase in MCA peak systolic velocity, suggests that cerebral flow metabolism coupling remained intact during rewarming.

Measuring Stroke Volume: Impedance Cardiography vs Phase-Contrast Magnetic Resonance Imaging.

BACKGROUND: Determination of cardiac output requires measurement of both heart rate and stroke volume. Techniques for measuring heart rate are widespread, and 1 technique for bedside monitoring of stroke volume is electrical impedance cardiography. OBJECTIVES: To determine the accuracy and precision of stroke volume measured via impedance cardiography and whether the technique can be used to detect trends. METHODS: Eleven healthy research participants (22-52 years old) were examined with simultaneous impedance cardiography and phase-contrast magnetic resonance imaging at rest and during exercise. Bland-Altman analysis with repeated-measures correction was used to compare stroke volumes determined with the 2 methods. The suitability of impedance cardiography for detecting trends in stroke volume was analyzed by using the Critchley radial limits of agreement method. RESULTS: Phase-contrast magnetic resonance imaging indicated a mean stroke volume of 87 (SD, 16) mL at rest; in 9 volunteers, it changed during exercise (P = .04 to P < .001); in 2 volunteers, it did not (P = .32, P = .06). For the range of stroke-volume measurements (60-122 mL), impedance cardiography yielded underestimates of stroke volumes at the low end (bias, -17 mL) and overestimates at the high end (bias, +17 mL; P < .001). Corresponding 95% limits of agreement were 64 mL, a 73% overestimate or underestimate of stroke volume at rest. Critchley radial limits of agreement indicated poor concordance of stroke-volume trends. CONCLUSIONS: Impedance cardiography had low accuracy and precision in measuring absolute stroke volume and was a poor detector of stroke-volume trends.

Changes in cardiac output and cerebral oxygenation during prone and supine sleep positioning in healthy term infants.

OBJECTIVE: To investigate the changes in systemic and cerebral haemodynamics between supine and prone sleep in healthy term infants during the early postnatal period. DESIGN/METHODS: Healthy term infants without congenital anomalies, patent ductus arteriosus and/or small for gestational age status were enrolled. Infants were placed in supine (SP1), prone (PP) and back in supine (SP2) position for 15 min each while asleep. Cardiac output (CO) and stroke volume (SV) were assessed by electrical velocimetry (EV) and echocardiography (echo), and cerebral regional oxygen saturation (CrSO2) in the frontal lobes was monitored by near-infrared spectroscopy. Heart rate (HR) and SpO2 were continuously monitored by conventional monitoring. RESULTS: In 34 healthy term infants (mean age 3.7±1.2 days; 16 females), 66 sets of serial CO measurements (34 EV and 32 echo) in three sleep positions were obtained. Mean COEV and COecho were 182±57 (SP1), 170±50 (PP) and 177±54 (SP2), and 193±48 (SP1), 174±40 (PP) and 192±50 (SP2) mL/kg/min, respectively. Mean SVEV and SVecho were 1.46±0.47 (SP1), 1.36±0.38 (PP) and 1.37±0.39 (SP2), and 1.54±40 (SP1), 1.38±0.38 (PP) and 1.51±0.41 (SP2) mL/kg, respectively. Repeated measures analysis of variance revealed a decrease in CO and SV during prone positions by both EV and echo, while HR, SpO2 and CrSO2 did not change. Thirty-eight per cent of the CO measurements decreased≥10% during prone positioning. CONCLUSIONS: In healthy term infants, CO decreases in prone position due to a decrease in SV and not HR. CO recovers when placed back in supine. However, frontal lobe CrSO2 does not change in the different positions.

Transitional Hemodynamics in Preterm Neonates: Clinical Relevance.

BACKGROUND: Each newborn enters this world facing tremendous respiratory, hemodynamic and neuroendocrine challenges while going through drastic physiological changes during the process of adaption from fetal to postnatal life. Even though the vast majority of term infants transition smoothly without apparent consequences, this task becomes increasingly arduous for the extremely preterm infant. METHODS & RESULTS: This article reviews the physiology and pathophysiology of cardiovascular adaptation of the very preterm neonate. In particular it describes the physiology of fetal circulation, summarizes the hemodynamic changes occurring during preterm births and discusses the impact of the most frequently seen clinical scenarios that place additional burden on the premature infant during immediate transition. Finally an emphasis is placed on discussing common clinical dilemmas and practical aspects of developmental hemodynamics such as neonatal hypotension and patent ductus arteriosus; clinical presentations the neonatologist encounters on a daily basis. CONCLUSION: The review provides a physiology-based view on the hemodynamics of the immediate postnatal transitional period.

"Tele-rounding" with a remotely controlled mobile robot in the neonatal intensive care unit.

OBJECTIVE: To investigate the feasibility of 'tele-rounding' in the neonatal intensive care. METHODS: In this prospective study utilizing telemedicine technology in the NICU for daily patient bedside rounds ('tele-rounds'), twenty pairs of neonates were matched according to gestational age, diagnoses, and disease severity. One patient was cared for by the on-site NICU team lead by an on-site neonatologist. The other patient was cared for by the on-site team but led by an off-site neonatologist using a remote-controlled robot. Patient rounding data, clinical outcomes, length of stay, and hospital costs were compared between the two groups. Parents and staff were also surveyed about their satisfaction with telemedicine. RESULTS: Except for one parameter, no significant differences in care or outcomes were found between patients cared for by either neonatologist. The exception was the time the off-site neonatologist spent on the patient encounter compared to the on-site neonatologist (median [interquartile range]), (5 minutes [5, 6] vs. 8 minutes [7, 10.5], p = 0.002). This difference was due primarily to time needed to operate and maneuver the robot or occasionally to slower or dropped connection to the Internet. There were positive perceptions of telemedicine among both parents and NICU staff. CONCLUSION: As long as direct bedside care providers are available, remote-controlled, robotic telemedicine technology can be utilized by neonatologists to perform daily patient rounds in the neonatal intensive care unit.

Prediction of Hemodynamic Response to Epinephrine via Model-Based System Identification.

In this study, we present a system identification approach to the mathematical modeling of hemodynamic responses to vasopressor-inotrope agents. We developed a hybrid model called the latency-dose-response-cardiovascular (LDC) model that incorporated 1) a low-order lumped latency model to reproduce the delay associated with the transport of vasopressor-inotrope agent and the onset of physiological effect, 2) phenomenological dose-response models to dictate the steady-state inotropic, chronotropic, and vasoactive responses as a function of vasopressor-inotrope dose, and 3) a physiological cardiovascular model to translate the agent's actions into the ultimate response of blood pressure. We assessed the validity of the LDC model to fit vasopressor-inotrope dose-response data using data collected from five piglet subjects during variable epinephrine infusion rates. The results suggested that the LDC model was viable in modeling the subjects' dynamic responses: After tuning the model to each subject, the r (2) values for measured versus model-predicted mean arterial pressure were consistently higher than 0.73. The results also suggested that intersubject variability in the dose-response models, rather than the latency models, had significantly more impact on the model's predictive capability: Fixing the latency model to population-averaged parameter values resulted in r(2) values higher than 0.57 between measured versus model-predicted mean arterial pressure, while fixing the dose-response model to population-averaged parameter values yielded nonphysiological predictions of mean arterial pressure. We conclude that the dose-response relationship must be individualized, whereas a population-averaged latency-model may be acceptable with minimal loss of model fidelity.

Hemodynamic monitoring of the critically ill neonate: An eye on the future.

By continuous assessment of dynamic changes in systemic and regional perfusion during transition to extrauterine life and beyond, comprehensive neonatal hemodynamic monitoring creates numerous opportunities for both clinical and research applications. In particular, it has the potential of providing additional details about physiologic interactions among the key hemodynamic factors regulating systemic blood flow and blood flow distribution along with the subtle changes that are frequently transient in nature and would not be detected without such systems in place. The data can then be applied for predictive mathematical modeling and validation of physiologically realistic computer models aiming to identify patient subgroups at higher risk for adverse outcomes and/or predicting the response to a particular perturbation or therapeutic intervention. Another emerging application that opens an entirely new era in hemodynamic research is the use of the physiometric data obtained by the monitoring and data acquisition systems in conjunction with genomic information.

Evidence-based versus pathophysiology-based approach to diagnosis and treatment of neonatal cardiovascular compromise.

With the advances in biomedical research and neonatal intensive care, our understanding of cardiovascular developmental physiology and pathophysiology has significantly improved during the last few decades. Despite this progress, the current management of circulatory compromise depends primarily on experts' opinions rather than high level of evidence. The lack of reliable, accurate, continuous and preferably non-invasive monitoring techniques has further limited our ability to collect the information needed for the design and execution of more sophisticated clinical trials with a better chance to provide the evidence we need. Given the lack of randomized, placebo-controlled trials investigating clinically relevant outcomes of novel treatments of neonatal cardiovascular compromise, we must now use the available lower level of evidence and our present understanding of developmental physiology and pathophysiology when providing cardiovascular supportive care to critically ill neonates. However, with recent advances in cardiovascular monitoring capabilities, direct and more objective assessment of the changes in cardiovascular function, organ blood flow, and tissue oxygenation have become possible. These advances have helped in our clinical assessment and enabled us to start designing more sophisticated interventional clinical trials using clinically relevant endpoints.

Hemodynamic antecedents of peri/intraventricular hemorrhage in very preterm neonates.

Novel hemodynamic monitoring technologies have contributed to the understanding of developmental cardiovascular physiology and pathophysiology in general, and of developmental hemodynamics in particular. Hemodynamic disturbances play a significant role in the pathogenesis of peri/intraventricular hemorrhage (P/IVH) in preterm infants. Immaturity of the myocardium, delayed and incomplete cardiopulmonary transition, sustained patency of the ductus arteriosus, and unintended consequences of respiratory and cardiovascular supportive care are all likely to be involved in the presentation of low cardiac output syndrome and decreased organ blood flow in a large number of very preterm neonates (gestational age ≤28 weeks). Forebrain vessels in very preterm infants may not have achieved a "high-priority vasculature" status at the time of delivery; in these patients, forebrain perfusion is not protected during the compensated phase of shock. Reperfusion may be attenuated by the careful use of medications decreasing cerebrovascular reactivity, thus providing a potential target for the development of careful pharmacological support of transitional hemodynamics in selected patients at high risk for the development of P/IVH.

Modeling of neonatal hemodynamics during PDA closure.

The transition of the fetus at birth to extrauterine life is an extremely complex process. As part of the hemodynamic transition, the closure of ductus arteriosus, a fetal shunt, is among the key steps to achieve normal postnatal cardiovascular function. However, significant gaps remain in our knowledge pertaining to the hemodynamics of normal ductal closure, and in case of failure of closure, to the hemodynamic consequences and treatment of the patent ductus arteriosus (PDA) in preterm infants. This paper presents a mathematical model of a newborn's cardiovascular system with five peripheral organ systems, the ductus arteriosus, and the baroreceptor reflex. We present the hemodynamic findings during simulation of sudden ductal closure, an event seen in real life when the PDA is closed surgically. The results of our model match the clinical data.

Changes in mean arterial blood pressure during sildenafil use in neonates with meconium aspiration syndrome or sepsis.

The aim of this study was to evaluate changes in mean blood pressure (MBP) in late preterm and term newborns with meconium aspiration syndrome (MAS) or sepsis who, in addition to inhaled nitric oxide (iNO), received enteral sildenafil for treatment of persistent pulmonary hypertension of the newborn. Data on sildenafil dosing, MBP, and vasopressor/inotrope use were collected for 72 hours after initiation of sildenafil. Groups were compared between "low dose" (<3 mg·kg·d) versus "high dose" (≥ 3 mg·kg·d) and "early" (<7 postnatal days) versus "late" (≥ 7 postnatal days) administration of sildenafil. Seventeen patients were identified. Ten and 7 patients received "low-dose" and "high-dose" sildenafil, respectively, and 8 and 9 patients were started on sildenafil "early" and "late," respectively. At the doses used, sildenafil treatment of infants with MAS and sepsis was not associated with changes in MBP. In addition, vasopressor/inotropic support was weaned in all groups. During the first 72 hours of enteral sildenafil administration in neonates with pulmonary hypertension of the newborn secondary to MAS or sepsis, no significant decrease in MBP or increase in vasopressor/inotrope requirement occurred.