Brain cortical assessment by MRI in fetuses with left congenital diaphragmatic hernia.

OBJECTIVE: To evaluate fetal brain development using MRI (magnetic resonance imaging) in CDH (congenital diaphragmatic hernia). METHODS: 52 isolated left CDH and 104 control fetuses were imaged using MRI. Brain morphometry (Biparietal diameter-BPD, brain fronto-occipital diameter-BFOD, third ventricle, posterior ventricles, transcerebellar diameter-TCD, anteroposterior and craniocaudal cerebellar vermis diameter-AP and CC) and cortical structures (bilateral cingulate fissure-CF, insular fissure-IF, insular depth - ID) were compared with controls using Mann-Whitney test. RESULTS: Median gestational age at MRI (p = 0.95)and the median biparietal diameter (p = 0.737) were comparable. Among morphometric parameters, only the brain fronto-occipital diameter was significantly smaller in CDH (p = 0.001) and the third ventricle was significantly greater in CDH (<0.0001). Among cortical structures, the cingulate and insular fissures were significantly deeper in CDH fetuses (p < 0.0001) as the insular depth ID was smaller in CDH (p < 0.03). CONCLUSIONS: CDH fetuses have a smaller fronto-occipital diameter, reduced insular depth, deeper cingulate and insular fissure, and greater third ventricle width as compared to controls. These findings suggest that left CDH may have an impact on fetal brain development with an overall reduction in brain volume.

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension.

Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers' understanding of the pathophysiology of CDH.

Hemodynamic Assessment of a Large Pulmonary Arteriovenous Malformation in a Neonate: Case Report and Review of Literature.

Herein we report the case of a neonate with a prenatally diagnosed large pulmonary arteriovenous malformation, managed with minimally invasive hemodynamic monitoring in our Neonatal Intensive Care Unit. The combination of Near-Infrared Spectroscopy and Pressure Recording Analytical Method could guide neonatal management of critical cases of vascular anomalies: immediate data are offered to clinicians, from which therapeutic decisions such as timing of surgical resection are made to achieve a positive outcome. We also systemically collected and summarized information on patients' characteristics of previous cases reported in literature to data, and we compared them to our case.

Neonatal limb ischemia: caudal blockade and NIRS monitoring.

The treatment of neonatal limb ischemia (LI) is challenging for neonatologists. Peripheral nerve blockade (PNB), alone or in association with other therapies, represents a valid therapy in case of vascular spasm or thromboembolic events responsible for LI. In the present case report, we describe the clinical history of a preterm neonate with catheter-related thrombosis of the left leg. PNB was not performed according to the traditional technique but rather by a peridural catheter left in situ for 9 days with a continuous infusion of ropivacaine. In conclusion, the effectiveness of this approach was confirmed by the contemporary near-infrared spectroscopy monitoring, documenting gradual improvement of leg perfusion.

A new variant in the GATA6 gene associated with tracheoesophageal fistula, pulmonary vein stenosis and neonatal diabetes.

INTRODUCTION: GATA6 is a gene that encodes a transcription factor with a key role in the development of several organ systems, including the development of the pancreas. It is associated with neonatal diabetes but also with other extra-pancreatic anomalies. CASE PRESENTATION: This report describes the association of tracheoesophageal fistula (TEF), pulmonary vein stenosis (PVS), and neonatal diabetes caused by a novel mutation of the GATA6 gene in a small-for-gestational-age male neonate born at 32 weeks of gestation. Next-Generation Sequencing revealed the novel heterozygous variant c.1502C>G in the GATA6 gene, which determines the introduction of the premature stop codon p.Ser501Ter at the protein level. This de novo nonsense variant was not detected in the analyzed parental DNA samples and has not been previously described in the literature. At about two months of life, a PVS was suspected. The PVS progressively increased with the development of an intramural component, resulting in severe postcapillary pulmonary hypertension. The child died at about 4 months of life. CONCLUSION: TEF can be associated with GATA6 variants. In the case of neonatal diabetes and TEF, neonatologists should be aware of this association and should also investigate the child for complex congenital heart disorders, such as in our case, with a cardiac computed tomography.

Early vasopressin infusion improves oxygenation in infants with congenital diaphragmatic hernia.

Objective: Congenital Diaphragmatic Hernia (CDH) is a complex disease including a diaphragmatic defect, lung hypoplasia, and pulmonary hypertension. Despite its increasing use in neonates, the literature on the use of vasopressin in neonates is limited. The aim of this work is to analyze the changes in clinical and hemodynamic variables in a cohort of CDH infants treated with vasopressin. Methods: Among CDH infants managed at the Neonatal Intensive Care Unit (NICU) of our hospital from May 2014 to January 2019, all infants who were treated with vasopressin, because of systemic hypotension and pulmonary hypertension, were enrolled in this retrospective study. The primary outcome was the change in oxygenation index (OI) after the start of the infusion of vasopressin. The secondary outcomes were the changes in cerebral and splanchnic fractional tissue oxygen extraction (FTOEc and FTOEs) at near-infrared spectroscopy, to understand the balance between oxygen supply and tissue oxygen consumption after the start of vasopressin infusion. We also reported as secondary outcomes the changes in ratio of arterial oxygen partial pressure (PaO2) to fraction of inspired oxygen (FiO2), heart rate, mean arterial pressure, serum pH, and serum sodium. Results: We included 27 patients with isolated CDH who received vasopressin administration. OI dramatically dropped when vasopressin infusion started, with a significant reduction according to ANOVA for repeated measures (p = 0.003). A global significant improvement in FTOEc and FTOEs was detected (p = 0.009 and p = 0.004, respectively) as a significant reduction in heart rate (p = 0.019). A global significant improvement in PaO2/FiO2 ratio was observed (p < 0.001) and also at all time points: at 6 h since infusion (p = 0.015), 12 h (p = 0.009), and 24 h (p = 0.006), respectively. A significant reduction in sodium levels was observed as expected side effect (p = 0.012). No significant changes were observed in the remaining outcomes. Conclusion: Our data suggest that starting early vasopressin infusion in CDH infants with pulmonary hypertension could improve oxygenation index and near-infrared spectroscopy after 12 and 24 h of infusion. These pilot data represent a background for planning future larger randomized trials to evaluate the efficacy and safety of vasopressin for the CDH population.

Use of levosimendan in hemodynamic management of heart failure in two neonates with intracranial arteriovenous shunts: a case series.

BACKGROUND: The hemodynamic status of newborns with intracranial arteriovenous shunts (AVSs) may be extremely complex. Mini-invasive hemodynamic monitoring through innovative techniques such as Near-Infrared Spectroscopy (NIRS) and Pressure Recording Analytical Method (PRAM) may help in understanding hemodynamics in newborns with AVSs. Levosimendan is a calcium sensitizer and inodilator, and it is known to improve ventricular function, but its use in newborns is limited. In our cases, we evaluated the effect of levosimendan on hemodynamics through NIRS and PRAM. CASE PRESENTATION: Herein, we report the cases of two neonates with intracranial arteriovenous shunts, in whom we used levosimendan to manage cardiac failure refractory to conventional treatment. Levosimendan was used at a dosage of 0.1 mcg/kg/min for 72 h. Combined use of NIRS and PRAM helped in real-time monitoring of hemodynamic effects; in particular, levosimendan determined significant improvement in myocardium contractility as well as a reduction of heart rate. CONCLUSION: In two neonatal cases of AVSs, levosimendan led to an overall hemodynamic stabilization, documented by the combination of NIRS and PRAM. Our results suggest introducing levosimendan as a second-line treatment in cases of severe cardiac dysfunction due to AVSs without improvement using standard treatment strategies. Future prospective and larger studies are highly warranted.

Post-operative ventilation strategies after surgical repair in neonates with esophageal atresia: A retrospective cohort study.

BACKGROUND: Infants affected by Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) may require non-invasive ventilation (NIV) in the post-operative period after elective extubation, especially if born preterm. The aim of the paper is to evaluate the role of different ventilation strategies on anastomotic complications, specifically on anastomotic leak (AL). MATERIALS AND METHODS: Retrospective single Institution study, including all consecutive neonates affected by EA with or without TEF in a 5-year period study (from 2014 to 2018). Only infants with a primary anastomosis were included in the study. All infants were mechanically ventilated after surgery and electively extubated after 6-7 days. The duration of invasive ventilation was decided on a case-by-case basis after surgery, based on the pre-operative esophageal gap and intraoperative findings. The need for non-invasive ventilation (NCPAP, NIPPV, and HHHFNC) after extubation and extubation failure with the need for mechanical ventilation in the post-operative period were assessed. The primary outcome evaluated was the rate of anastomotic leak. RESULTS: 102 EA/TEF infants were managed in the study period. Sixty-seven underwent primary anastomosis. Of these, 29 (43.3%) were born preterm. Patients who required ventilation (n = 32) had a significantly lower gestational age as well as birthweight (respectively p = 0.007 and p = 0.041). 4/67 patients had an AL after surgical repair, with no statistical differences among post-operative ventilation strategies. CONCLUSION: We found no significant differences in the rate of anastomotic leak (AL) according to post-operative ventilation strategies in neonates operated on for EA/TEF.

Current Strategies to Optimize Nutrition and Growth in Newborns and Infants with Congenital Heart Disease: A Narrative Review.

(1) Objective: This review aims to identify the clinical and practical barriers to optimizing nutrition in newborn infants with congenital heart disease (CHD) and to describe updated evidence-based recommendations for clinical and nutritional management of these patients in a narrative review. (2) Research Methods and Procedures: We conducted a search of the relevant literature published from 2000 to December 2021. (3) Results: CHD patients undergo several nutritional challenges related to the underlying cardiac disease anomaly, the potential increased risk of NEC, and delayed enteral feeding, resulting in inadequate energy intake and sub-optimal growth, increased morbidity and mortality. (4) Conclusions: To optimize nutrition and growth in newborn infants with CHD, standardized protocols should be implemented. Regular nutritional and growth assessment with a multi-disciplinary team is essential. We propose a decisional algorithm that may represent a potentially useful tool to guide clinicians to optimize growth and nutrition.

Morphometric Analysis of Brain in Newborn with Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is a severe pediatric disorder with herniation of abdominal viscera into the thoracic cavity. Since neurodevelopmental impairment constitutes a common outcome, we performed morphometric magnetic resonance imaging (MRI) analysis on CDH infants to investigate cortical parameters such as cortical thickness (CT) and local gyrification index (LGI). By assessing CT and LGI distributions and their correlations with variables which might have an impact on oxygen delivery (total lung volume, TLV), we aimed to detect how altered perfusion affects cortical development in CDH. A group of CDH patients received both prenatal (i.e., fetal stage) and postnatal MRI. From postnatal high-resolution T2-weighted images, mean CT and LGI distributions of 16 CDH were computed and statistically compared to those of 13 controls. Moreover, TLV measures obtained from fetal MRI were further correlated to LGI. Compared to controls, CDH infants exhibited areas of hypogiria within bilateral fronto-temporo-parietal labels, while no differences were found for CT. LGI significantly correlated with TLV within bilateral temporal lobes and left frontal lobe, involving language- and auditory-related brain areas. Although the causes of neurodevelopmental impairment in CDH are still unclear, our results may suggest their link with altered cortical maturation and possible impaired oxygen perfusion.

Mild hypothermia and hemorrhagic lesions in neonates with hypoxic-ischemic encephalopathy: experience in an outborn center.

OBJECTIVE: Therapeutic hypothermia (TH) started within six hours from birth has been shown to improve neurodevelopmental outcomes in newborns with moderate-to-severe hypoxic-ischemic encephalopathy. METHODS: Twenty-nine consecutive newborns treated with whole body cooling at the Bambino Gesú Children's Hospital between March 2011 and December 2012 were included in this study. All infants were out-born neonates. Passive cooling was always started at the birth center and continued during transportation. Pre- and post-transport risk index of physiological stability (TRIPS) scores were calculated for each patient to evaluate the impact of the transportation. Magnetic resonance imaging (MRI) was performed within 10 days of life to investigate the presence of brain injury. RESULTS: Among the 26 survivors, 14 had no detectable lesions and 12 presented with brain injury on MRI. Four babies presented with cerebral bleeding. Babies with cerebral hemorrhage had a worse pre-transport TRIPS score, but among these neonates no worsening between pre and post-transport score was registered. CONCLUSION: The presence of cerebral hemorrhagic lesions seemed to be related to the initial clinical conditions of the baby rather than to the transport itself. Our data confirm that TH performed in an out-born center is efficient and safe.

Effects of ventilation modalities on near-infrared spectroscopy in surgically corrected CDH infants.

BACKGROUND: Near-infrared spectroscopy (NIRS) is a noninvasive technique for monitoring tissue oxygenation and perfusion. The aim of this study was to evaluate cerebral and splanchnic NIRS changes in CDH operated infants enrolled into the VICI trial and therefore randomized for ventilatory modalities. MATERIALS AND METHODS: CDH newborns enrolled into the VICI trial (Netherlands Trial Register, NTR 1310) were randomized at birth for high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CMV) according to the trial. Cerebral oxygenation (rSO2C) and splanchnic oxygenation (rSO2S) were obtained by NIRS (INVOS 5100; Somanetics, Troy, MI) before and after surgery. Variations in rSO2C and rSO2S were evaluated. Mann-Whitney test and one-way ANOVA were used as appropriate. p<0.05 was considered significant. RESULTS: Thirteen VICI trial patients underwent surgical repair between March 2011 and December 2012, and were enrolled in the study. Seven patients were assigned to HFOV and six to CMV group respectively. During surgery, a significant reduction in rSO2C (p=0.0001) and rSO2S (p=0.005) were observed. HFOV patients experienced prolonged reduction in rSO2C value (p=0.003) while rSO2S did not vary between HFOV and CMV (p=0.94). CONCLUSIONS: Surgical CDH repair was associated with decrease of cerebral and splanchnic oxygenation, regardless of ventilation. Patients ventilated by HFOV need a longer time interval to recovery normal rSO2C values, than those ventilated by CMV. This may be owing to a different impact of HFOV on patients' hemodynamic status with a higher impairment on total venous return and its negative consequences on cardiac output.

Near infrared spectroscopy: experience on esophageal atresia infants.

OBJECTIVE: Near infrared spectroscopy (NIRS) gradually became the gold standard to guide anesthetic conduction during cardiac surgery, and nowadays, it is commonly utilized to monitor cerebral oxygenation during invasive procedures. Preterm babies also benefit from this non-invasive monitoring to prevent neurological sequelae. However, few data are available on NIRS perioperative changes in newborn operated on for major non-cardiac malformations. Aim of the present study is to evaluate the usefulness of NIRS assessment during and after esophageal atresia (EA) correction and its correlation with clinical behavior. PATIENTS AND METHODS: All patients treated for EA from May 2011 were prospectively enrolled in the study. All infants underwent "open" correction of EA and cerebral and splanchnic NIRS was applied up to 48h after surgery. Body temperature, blood pressure, pH, paSO2, paCO2, and urine output, were recorded during NIRS registration. Mann-Whitney test and 1-way ANOVA (Kruskal-Wallis and Dunn's multiple comparison tests) were used as appropriate. RESULTS: Seventeen patients were enrolled into the study and 13 were available for the analysis. Four patients were excluded because of poor NIRS registration. Cerebral and renal NIRS values significantly decreased at 24h post-operatively (p<0.05). Interestingly, all parameters studied as possible confounders in NIRS remained stable during the study period. Urine output significantly decreased. CONCLUSION: Our data confirmed that perioperative monitoring of tissue oxygenation during neonatal esophageal surgery is feasible. Cerebral and renal NIRS evaluation, as for cardiac patients, may guide anesthetic conduction and postoperative care. Out data suggest a newly observed hemodynamic reorganization during esophageal surgery involving renal and, probably, splanchnic blood flow redistribution, demonstrated by the observed subsequent significant post-operative transitory decrease in urinary output. Reducing the decrement in cerebral and renal NIRS values may improve, and ideally eliminate, the well-known late sequelae linked to hemodynamic changes during surgery. More studies are needed to better understand the causes of the NIRS described hemodynamic changes and, therefore, correct them.

Functional residual capacity (FRC) and lung clearance index (LCI) in mechanically ventilated infants: application in the newborn with congenital diaphragmatic hernia (CDH).

INTRODUCTION: Functional residual capacity (FRC) and lung clearance index (LCI) are sensitive parameters for early detection of airway disease in infancy. The closed helium dilution method has been applied to assess lung volume and ventilation inhomogeneity (VI) in spontaneously breathing infants. AIMS: The aims of this study were as follows: (1) to assess applicability of the helium gas dilution technique in mechanically ventilated infants with high-risk congenital diaphragmatic hernia (CDH) and to evaluate changes in breathing patterns, lung volume, and VI during the first days of life before and after surgery, and (2) to analyze the possible correlation between changes in lung volume, cerebral hemodynamics, and oxygenation before and after surgical correction of CDH through near-infrared spectroscopy (NIRS) monitoring. METHODS: Lung function tests were performed by multibreath washout traces with an ultrasonic flowmeter and helium gas dilution technique. For all babies, three acceptable FRC and LCI measurements were collected for each test (mean and SD of three measurements were calculated) before surgery (T0), 24 h after surgery (T1) during mechanical ventilation, and within 24 h after extubation in spontaneous breathing (T2). Cerebral and splanchnic hemodynamics were continuously monitored by NIRS during mechanical ventilation to evaluate relationships between changes in lung volume and capillary-venous oxyhemoglobin saturation in tissues. Fraction of inspired oxygen delivered was adjusted to keep oxygen saturation between 90% and 95%. RESULTS: Thirteen CDH infants were studied; median GA = 38 weeks (range 35-41) and median BW = 3000 g (range 1850-3670). FRC and LCI significantly improved after extubation when compared with pre-surgical values. No differences were found in tidal volume (Vt) and NIRS monitoring before and after surgery and after extubation. Neither LCI nor FRC was correlated with NIRS values. CONCLUSIONS: Helium gas dilution technique is an applicable and reliable technique to measure lung volumes and ventilation inhomogeneity also in ventilated infants. NIRS is a non-invasive technique to monitor tissue oxygenation during surgery and mechanical ventilation. In CDH newborns these preliminary data show an improvement in both FRC and LCI after extubation.

The scenarios of shock in newborn infants.

Shock defines a complex dysfunction of organ perfusion, that produces a status of cellular energy failure, resulting from an insufficient supply of oxygen and nutrients to tissues. The diagnosis of shock is very difficult because of the lack of sufficiently sensitive and specific clinical criteria, and is substantially based on the demonstration of an arterial hypotension, an indicator unfit to detect the organ hypoperfusion. It determines the necessity of firmly introducing in the diagnostic run the functional echocardiography, the near infrared spectroscopy and the amplitude – integrated electroencephalography, etc., in the monitoring of the critical newborn. In order to simplify the problem, the authors identify the clinical scenarios of the newborn's shock to enhance the different pathogenetic moments and to build up appropriate therapeutic algorithms, without forgetting that at present there is no evidence that treatment of shock improves outcomes, despite the large amount of the studies conducted on this topic.

The physiopathology of the patent ductus arteriosus.

Patent ductus arteriosus (PDA) remains a frequent problem for the very low birth weight infants. Many questions about the role of PDA, the best method of diagnosing it and the appropriate timing of treatment have been, at time, not completely answered. What we now know is that the left to right shunt appears very soon after birth and, if the ductus remains open, results in a progressively lung over circulation and a left ventricular volume overload. Despite the immature myocardium, the heart is able to increase its cardiac output, mainly through an increase in stroke volume, even in extremely preterm newborns. The increment of stroke volume does not increase or maintain an effective systemic perfusion and with the time it will become unproductive. Both animal and human studies showed a compromise of organ blood flow, with the development of systemic hypotension, steal phenomena, organ hypoperfusion, and ultimately congestive heart failure.