Serum cortisol concentrations during induced hypothermia for perinatal asphyxia are associated with neurological outcome in human infants.

Birth asphyxia is a cause of neonatal death or adverse neurological sequelae. Biomarkers can be useful to clinicians in order to optimize intensive care management and communication of prognosis to parents. During perinatal adverse events, increased cortisol secretion is due to hypothalamo-pituitary-adrenal axis activation. We aimed to investigate if cortisol variations during therapeutic hypothermia are associated with neurodevelopmental outcome. We compared 18 cases (neonates with birth asphyxia) with 18 controls (healthy term newborns) and confirmed increased serum cortisol concentrations following the peri-partum adverse event. Among cases, we stratified patients according to neurological outcome at 18 months (group A - good; group B - adverse) and found that after 24 h of therapeutic hypothermia serum cortisol concentration was significantly lower in group A vs group B (28.7 ng/mL vs 344 ng/mL, *p = 0.01). In group B serum, cortisol concentration decreased more gradually during therapeutic hypothermia. We conclude that monitoring serum cortisol concentration during neonatal therapeutic hypothermia can add information to clinical evaluation of neonates with birth asphyxia; cortisol values after the first 24 h of hypothermia can be a biomarker associated with neurodevelopmental outcome at 18 months of age.

An active one-lobe pulmonary simulator with compliance control for medical training in neonatal mechanical ventilation.

Mechanical ventilation is a current support therapy for newborns affected by respiratory diseases. However, several side effects have been observed after treatment, making it mandatory for physicians to determine more suitable approaches. High fidelity simulation is an efficient educational technique that recreates clinical experience. The aim of the present study is the design of an innovative and versatile neonatal respiratory simulator which could be useful in training courses for physicians and nurses as for mechanical ventilation. A single chamber prototype, reproducing a pulmonary lobe both in size and function, was designed and assembled. Volume and pressure within the chamber can be tuned by the operator through the device control system, in order to simulate both spontaneous and assisted breathing. An innovative software-based simulator for training neonatologists and nurses within the continuing medical education program on respiratory disease management was validated. Following the clinical needs, three friendly graphic user interfaces were implemented for simulating three different clinical scenarios (spontaneous breathing, controlled breathing and triggered/assisted ventilation modalities) thus providing physicians with an active experience. The proposed pulmonary simulator has the potential to be included in the range of computer-driven technologies used in medical training, adding novel functions and improving simulation results.

Lutein administration to pregnant women with gestational diabetes mellitus is associated to a decrease of oxidative stress in newborns.

Oxidative stress (OS) is defined as an imbalance between pro- and antioxidant factors that can lead to cellular and tissue damage. Under condition of gestational diabetes, OS is exacerbated and can cause vascular dysfunction in the placenta, leading to fetal and perinatal complications. We investigated the oxidative status of diabetic pregnant women and of their babies. A group of those diabetic women received lutein, and another group did not receive anything. In order to verify a possible antioxidant function of lutein, we compared the OS values of the two groups. OS appeared lower in treated gravidas than in untreated ones; however, there was not a statistically significant difference between the two groups. As far as newborns are concerned, there was a significant difference of OS values between babies born to mothers treated with lutein and newborns to mothers untreated at 2 h of life. However, at 48 h, there was not a significant difference between the two groups. In conclusion, lutein administration during pregnancy significantly reduced neonatal OS at birth. Further studies are necessary to evaluate the effects of combined administration to mother and infants.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI).

BACKGROUND: Despite progresses in neonatal care, the mortality and the incidence of neuro-motor disability after perinatal asphyxia have failed to show substantial improvements. In countries with a high level of perinatal care, the incidence of asphyxia responsible for moderate or severe encephalopathy is still 2-3 per 1000 term newborns. Recent trials have demonstrated that moderate hypothermia, started within 6 hours after birth and protracted for 72 hours, can significantly improve survival and reduce neurologic impairment in neonates with hypoxic-ischemic encephalopathy. It is not currently known whether neuroprotective drugs can further improve the beneficial effects of hypothermia. Topiramate has been proven to reduce brain injury in animal models of neonatal hypoxic ischemic encephalopathy. However, the association of mild hypothermia and topiramate treatment has never been studied in human newborns. The objective of this research project is to evaluate, through a multicenter randomized controlled trial, whether the efficacy of moderate hypothermia can be increased by concomitant topiramate treatment. METHODS/DESIGN: Term newborns (gestational age ≥ 36 weeks and birth weight ≥ 1800 g) with precocious metabolic, clinical and electroencephalographic (EEG) signs of hypoxic-ischemic encephalopathy will be randomized, according to their EEG pattern, to receive topiramate added to standard treatment with moderate hypothermia or standard treatment alone. Topiramate will be administered at 10 mg/kg once a day for the first 3 days of life. Topiramate concentrations will be measured on serial dried blood spots. 64 participants will be recruited in the study. To evaluate the safety of topiramate administration, cardiac and respiratory parameters will be continuously monitored. Blood samplings will be performed to check renal, liver and metabolic balance. To evaluate the efficacy of topiramate, the neurologic outcome of enrolled newborns will be evaluated by serial neurologic and neuroradiologic examinations. Visual function will be evaluated by means of behavioural standardized tests. DISCUSSION: This pilot study will explore the possible therapeutic role of topiramate in combination with moderate hypothermia. Any favourable results of this research might open new perspectives about the reduction of cerebral damage in asphyxiated newborns.

The effects of preterm infant massage on brain electrical activity.

AIM: Early intervention programmes based on the manipulation of the extra-uterine environment have been used in preterm infants with the aim of improving development and functional outcome. Infant massage, among them, has proved effective for weight gain and reduced length of stay in the neonatal intensive care unit. We have recently shown that infant massage accelerates brain maturation of low-risk preterm infants without brain abnormalities as measured by global parameters of electroencephalography (EEG) activity. In the present study we further analyse the same cohort of preterm infants, testing the hypothesis that massage determines changes in EEG spectral activity, a highly sensitive index of brain maturation. METHOD: Infants were randomly allocated to a massage or comparison group. Intervention consisted of standard care only (comparison group) or standard care plus infant massage (massage group). Massage was started at around 10 days after birth and was provided for 12 days during a 2-week period. EEG was performed at around 1 and 4 weeks, i.e. before and after intervention. Spectral EEG analysis was performed on 80 seconds of active sleep, applying the fast Fourier transform on the signal obtained from eight monopolar derivations. RESULTS: The modification in global EEG spectral power between the two assessments was significantly different for the two groups, especially for the delta band activity; the spectral power did not change in massaged infants although, not surprisingly, it decreased significantly in the comparison group, as shown by previous studies. INTERPRETATION: We propose that massage intervention affects the maturation of brain electrical activity and favours a process more similar to that observed in utero in term infants.

Correlation between placental histopathology and fetal/neonatal outcome: chorioamnionitis and funisitis are associated to intraventricular haemorrage and retinopathy of prematurity in preterm newborns.

INTRODUCTION: Placental anatomopathologic lesions are usually associated with pregnancy complications and neonatal impaired outcome. PATIENTS AND METHODS: We included in our study 122 patients with gestational age of 26-35 weeks. From the analysis of three pathological aspects (chorioamnionitis, funisitis and chronic hypoxia), a score was assigned to each lesion depending on the severity of the alteration, to establish a correlation with an impaired neonatal outcome in preterm newborns. RESULTS: We found a correlation between chronic hypoxia and preeclampsia, intrauterine growth restriction and/or small-for-gestational age status at birth. Our results also showed the strong association of fetal placental inflammatory status (chorioamnionitis and funisitis) with premature rupture of membranes, very low birth weight, birth at/before 32 gestational weeks, late-onset sepsis, patent duct arteriosus, intraventricular haemorrhage (IVH) and retinopathy of prematurity (ROP). CONCLUSIONS: We confirm that placental lesions are associated with impaired pregnancy and neonatal outcome. During pregnancy it may be useful to identify some markers of inflammatory status and chronic hypoxia for an early diagnosis and a detailed monitoring of pregnancy course. Placental pathological analysis is very important to predict the risk of developing serious complications of preterm birth as ROP and IVH.

Massage accelerates brain development and the maturation of visual function.

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1.

Hand movements at 3 months predict later hemiplegia in term infants with neonatal cerebral infarction.

AIM: The aim of this study was to explore the predictive value of quantitative assessment of hand movements in 3-month-old infants after neonatal stroke. METHOD: Thirteen infants born at term (five females, eight males; mean gestational age 39.4wks, SD 1.19, range 37-41wks; mean birthweight 3240g, SD 203, range 2900-3570g) with neonatal arterial ischaemic cerebral infarction, and 13 healthy infants (mean gestational age 39.1wks, range 37-41wks, SD 1.26; mean birthweight 3190g, SD 259, range 2680-3490g) were enrolled in the study. The absolute frequency and the asymmetry of global hand opening and closing, wrist segmental movements, and independent digit movements were assessed from videotapes recorded at around 12 weeks. Neurological outcome was assessed when the infants were at least 18 months old using Touwen's neurological examination. RESULTS: Five of the 13 infants with neonatal stroke had normal neurological development, and eight had hemiplegia. Asymmetry of wrist segmental movements and the absolute frequency of independent digit movements were significantly different between infants with and without hemiplegia (p=0.006 and p=0.008, respectively). No differences were found in global hand movements. INTERPRETATION: We propose that the observed abnormalities of hand movements are the result of two different mechanisms: direct disruption of the corticospinal projection to the spinal cord, and altered modulation of the central pattern generators of general movements.

Drug addiction during pregnancy: correlations between the placental health and the newborn's outcome - elaboration of a predictive score.

During pregnancy, drug addiction represents one of the most dangerous situations. Each drug can badly affect the fetal development and, when the pregnancy is over, the negative influence continues in the newborn which is exposed to many risks, in particular the withdrawal syndrome. Since it is difficult to predict the newborn's outcome only on the basis of the kind of drug assumed by the mother during pregnancy, we propose the idea of a score based on the placenta's state of health. The aim of the study is to correlate the placental score to the withdrawal symptoms graveness. Our retrospective study includes 35 newborns exposed in uterus to illegal and legal drugs. We used the Finnegan's scoring system to quantify withdrawal symptoms and the placental score, based on the anatomopathological analysis, to assess the placenta's health. The newborns included in our study have been divided into two groups depending on the result of the placental score (< or =2 or > or =3). We found a significant statistical difference between the newborns whose placental score was low (< or =2) and those whose score was high (> or =3): the second group showed severe withdrawal symptoms for a longer time during the hospital stay (p = 0.014).

Technical realization of a sensorized neonatal intubation skill trainer for operators' retraining and a pilot study for its validation.

BACKGROUND: In neonatal endotracheal intubation, excessive pressure on soft tissues during laryngoscopy can determine permanent injury. Low-fidelity skill trainers do not give valid feedback about this issue. This study describes the technical realization and validation of an active neonatal intubation skill trainer providing objective feedback. METHODS: We studied expert health professionals' performances in neonatal intubation, underlining chance for procedure retraining. We identified the most critical points in epiglottis and dental arches and fixed commercial force sensors on chosen points on a ©Laerdal Neonatal Intubation Trainer. Our skill trainer was set up as a grade 3 on Cormack and Lehane's scale, i.e. a model of difficult intubation. An associated software provided real time sound feedback if pressure during laryngoscopy exceeded an established threshold. Pressure data were recorded in a database, for subsequent analysis with non-parametric statistical tests. We organized our study in two intubation sessions (5 attempts each one) for everyone of our participants, held 24 h apart. Between the two sessions, a debriefing phase took place. In addition, we gave our participants two interview, one at the beginning and one at the end of the study, to get information about our subjects and to have feedback about our design. RESULTS: We obtained statistical significant differences between consecutive attempts, with evidence of learning trends. Pressure on critical points was significantly lower during the second session (p < 0.0001). Epiglottis' sensor was the most stressed (p < 0.000001). We found a significant correlation between time spent for each attempt and pressures applied to the airways in the two sessions, more significant in the second one (shorter attempts with less pressure, rs = 0.603). CONCLUSIONS: Our skill trainer represents a reliable model of difficult intubation. Our results show its potential to optimize procedures related to the control of trauma risk and to improve personnel retraining.

Safety and efficacy of topiramate in neonates with hypoxic ischemic encephalopathy treated with hypothermia (NeoNATI): a feasibility study.

PURPOSE: To investigate the feasibility of a study based on treatment with topiramate (TPM) added to moderate hypothermia in newborns with hypoxic ischemic encephalopathy (HIE). MATERIALS AND METHODS: Multicenter randomized controlled trial. Term newborns with precocious metabolic, clinical and electroencephalographic (EEG) signs of HIE were selected according to their amplified integrated EEG pattern and randomized to receive either TPM (10 mg/kg once a day for the first three days of life) plus moderate hypothermia or hypothermia alone. Safety was assessed by monitoring cardiorespiratory parameters and blood samples collected to check renal, liver, metabolic balance and TPM pharmacokinetics. Efficacy was evaluated by the combined frequency of mortality and severe neurological disability as primary outcome. Incidence of magnetic resonance injury, epilepsy, blindness, hearing loss, neurodevelopment at 18-24 months of life was assessed as secondary outcomes. RESULTS: Forty-four asphyxiated newborns were enrolled in the study. Twenty one newborns (10 with moderate and 11 with severe HIE) were allocated to hypothermia plus TPM and 23 (12 moderate and 11 severe HIE) to hypothermia. No statistically or clinically significant differences were observed for safety, primary or secondary outcomes. However, a reduction in the prevalence of epilepsy was observed in newborns co-treated with TPM. CONCLUSIONS: Results of this pilot trial suggest that administration of TPM in newborns with HIE is safe but does not reduce the combined frequency of mortality and severe neurological disability. The role of TPM co-treatment in preventing subsequent epilepsy deserves further studies.

Does the assessment of general movements without video observation reliably predict neurological outcome?

OBJECTIVE: To assess the clinical value of a modified version, not employing video recording, of Precthl's method on the qualitative assessment of general movements (GMs) in preterm, term and young infants at neurological risk. MATERIALS AND METHODS: One-hundred and fifteen infants consecutively enrolled in our follow-up program were selected for the study (103 preterm and 12 term infants). While being video recorded, each infant's spontaneous motor activity was directly observed and documented using a written proforma. An evaluation of the video was later performed by a different assessor blind to the infant's clinical history. RESULTS: The correlation between the two techniques was significant both at writhing age (birth to 6 weeks post-term age) and at fidgety age (9-15 weeks post-term age). Both methods showed a very high sensitivity for the prediction of cerebral palsy, as no false negatives were observed. The direct assessment showed a lower specificity, particularly during the writhing period. CONCLUSIONS: These results support the use of the direct assessment of GMs when the full application of the standard video observation cannot be routinely applied, restraining the use of video recordings to the abnormal or doubtful cases. This may facilitate the wished integration of the assessment of spontaneous motility into more general protocols of neurological examination and into clinical follow-up programs.

Two Moroccan Sisters Presenting with a Severe Salt-Wasting Form of Congenital Adrenal Hyperplasia but Normal Female Genitalia.

We report the case of 2 sisters (46,XX) born from consanguineous Moroccan parents. Both sisters had normal female genitalia, but within 2 weeks after birth, they presented with a severe salt-wasting crisis. Hormonal investigations suggested the diagnosis of congenital adrenal hyperplasia, which was confirmed by subsequent molecular analysis to be caused by 3ß-hydroxysteroid dehydrogenase type 2 deficiency. Here, we discuss the main features like onset, possible complications, genetics, and replacement therapy of this rare disease.

Catheter and Laryngeal Mask Endotracheal Surfactant Therapy: the CALMEST approach as a novel MIST technique.

PURPOSE: Neonatal respiratory distress syndrome (RDS) is a major cause of mortality and morbidity among preterm infants. Although the INSURE (INtubation, SURfactant administration, Estubation) technique for surfactant replacement therapy is so far the gold standard method, over the last years new approaches have been studied, i.e. less invasive surfactant administration (LISA) or minimally invasive surfactant therapy (MIST). Here we propose an originally modified MIST, called CALMEST (Catheter And Laryngeal Mask Endotracheal Surfactant Therapy), using a particular laryngeal mask as a guide for a thin catheter to deliver surfactant directly in the trachea. MATERIALS AND METHODS: We performed a preliminary study on a mannequin and a subsequent in vivo pilot trial. RESULTS AND CONCLUSIONS: This novel procedure is quick, effective and well tolerated and might represent an improvement in reducing neonatal stress. Ultimately, CALMEST offers an alternative approach that could be extremely useful for medical staff with low expertise in laryngoscopy and intubation.

Effect of high-fidelity shoulder dystocia simulation on emergency obstetric skills and crew resource management skills among residents.

OBJECTIVE: To determine the effect of a simulation training program for residents in obstetrics and gynecology in terms of technical and nontechnical skills for the management of shoulder dystocia. METHODS: A prospective study was performed at a center in Italy in April-May 2015. Thirty-two obstetrics and gynecology residents were divided into two groups. Residents in the control group were immediately exposed to an emergency shoulder dystocia scenario, whereas those in the simulation group completed a 2-hour training session with the simulator before being exposed to the scenario. After 8weeks, the residents were again exposed to the shoulder dystocia scenario and reassessed. Participants were scored on their demonstration of technical and nontechnical skills. RESULTS: In the first set of scenarios, the mean score was higher in the simulation group than the control group in terms of both technical skills (P=0.008) and nontechnical skills (P<0.001). This difference was retained after 8weeks. CONCLUSION: High-fidelity simulation programs could be used for the training of residents in obstetrics and gynecology to diagnose and manage obstetric emergencies such as shoulder dystocia.

Comparative performances analysis of neonatal ventilators.

BACKGROUND: Mechanical ventilation is a therapeutic action for newborns with respiratory diseases but may have side effects. Correct equipment knowledge and training may limit human errors. We aimed to test different neonatal mechanical ventilators' performances by an acquisition module (a commercial pressure sensor plus an isolated chamber and a dedicated software). METHODS: The differences (ΔP) between peak pressure values and end-expiration pressure were investigated for each ventilator. We focused on discrepancies among measured and imposed pressure data. A statistical analysis was performed. RESULTS: We investigated the measured/imposed ΔP relation. The ΔP do not reveal univocal trends related to ventilation setting parameters and the data distributions were non-Gaussian. CONCLUSIONS: Measured ΔP represent a significant parameter in newborns' ventilation, due to the typical small volumes. The investigated ventilators showed different tendencies. Therefore, a deep specific knowledge of the intensive care devices is mandatory for caregivers to correctly exploit their operating principles.

Revised recommendations concerning palivizumab prophylaxis for respiratory syncytial virus (RSV).

Respiratory Syncytial Virus infections are one of the leading causes of severe respiratory diseases that require hospitalization and, in some cases, intensive care. Once resolved, there may be respiratory sequelae of varying severity. The lack of effective treatments for bronchiolitis and the lack of vaccines for RSV accentuate the role of prevention in decreasing the impact of this disease. Prevention of bronchiolitis strongly relies on the adoption of environment and the hygienic behavior measures; an additional prophylactic effect may be offered, in selected cases, by Palivizumab, a humanized monoclonal antibody produced by recombinant DNA technology, able to prevent RSV infection by blocking viral replication.After many years the Italian Society of Neonatology, on the basis of the most recent scientific knowledge, has decided to revise recommendations for the use of palivizumab in the prevention of RSV infection.

A novel simulator for mechanical ventilation in newborns: MEchatronic REspiratory System SImulator for Neonatal Applications.

Respiratory problems are among the main causes of mortality for preterm newborns with pulmonary diseases; mechanical ventilation provides standard care, but long-term complications are still largely reported. In this framework, continuous medical education is mandatory to correctly manage assistance devices. However, commercially available neonatal respiratory simulators are rarely suitable for representing anatomical and physiological conditions; a step toward high-fidelity simulation, therefore, is essential for nurses and neonatologists to acquire the practice needed without any risk. An innovative multi-compartmental infant respirator simulator based on a five-lobe model was developed to reproduce different physio-pathological conditions in infants and to simulate many different kinds of clinical scenarios. The work consisted of three phases: (1) a theoretical study and modeling phase, (2) a prototyping phase, and (3) testing of the simulation software during training courses. The neonatal pulmonary simulator produced allows the replication and evaluation of different mechanical ventilation modalities in infants suffering from many different kinds of respiratory physio-pathological conditions. In particular, the system provides variable compliances for each lobe in an independent manner and different resistance levels for the airway branches; moreover, it allows the trainer to simulate both autonomous and mechanically assisted respiratory cycles in newborns. The developed and tested simulator is a significant contribution to the field of medical simulation in neonatology, as it makes it possible to choose the best ventilation strategy and to perform fully aware management of ventilation parameters.

Human saliva as route of inter-human infection for mouse mammary tumor virus.

Etiology of human breast cancer is unknown, whereas the Mouse Mammary Tumor Virus (MMTV) is recognized as the etiologic agent of mouse mammary carcinoma. Moreover, this experimental model contributed substantially to our understanding of many biological aspects of the human disease. Several data strongly suggest a causative role of MMTV in humans, such as the presence of viral sequences in a high percentage of infiltrating breast carcinoma and in its preinvasive lesions, the production of viral particles in primary cultures of breast cancer, the ability of the virus to infect cells in culture. This paper demonstrates that MMTV is present in human saliva and salivary glands. MMTV presence was investigated by fluorescent PCR, RT-PCR, FISH, immunohistochemistry, and whole transcriptome analysis. Saliva was obtained from newborns, children, adults, and breast cancer patients. The saliva of newborns is MMTV-free, whereas MMTV is present in saliva of children (26.66%), healthy adults (10.60%), and breast cancer patients (57.14% as DNA and 33.9% as RNA). MMTV is also present in 8.10% of salivary glands. RNA-seq analysis performed on saliva of a breast cancer patient demonstrates a high expression of MMTV RNA in comparison to negative controls. The possibility of a contamination by murine DNA was excluded by murine mtDNA and IAP LTR PCR. These findings confirm the presence of MMTV in humans, strongly suggest saliva as route in inter-human infection, and support the hypothesis of a viral origin for human breast carcinoma.