Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentrated on prevention of the production of reactive oxygen species or free radicals (xanthine-oxidase-, nitric oxide synthase-, and prostaglandin inhibition), anti-inflammatory effects (erythropoietin, melatonin, Xenon) and anti-apoptotic interventions (nuclear factor kappa B- and c-jun N-terminal kinase inhibition); in a later stage stimulation of neurotrophic properties in the neonatal brain (erythropoietin, growth factors) can be targeted to promote neuronal and oligodendrocyte regeneration. Combination of pharmacological means of treatment with moderate hypothermia, which is accepted now as a meaningful therapy, is probably the next step in clinical treatment to fight post-asphyxial brain damage. Further studies should be directed at a more rational use of therapies by determining the optimal time and dose to inhibit the different potentially destructive molecular pathways or to enhance endogenous repair while at the same time avoiding adverse effects of the drugs used

Prevention, Reduction and Repair of Brain Injury of the Preterm Infant

Periventricular-intraventricular hemorrhages (PIVH) and (diffuse) white matter injury (WMI) are the most important acquired brain lesions of the very and extremely prematurely born neonate. Both carry a high risk for death or adverse neurodevelopmental outcome. The first part of the review discusses the standard of care and latest insights with respect to prevention and/or reduction of PIVH and WMI, taking into account their etiopathogenesis which is tightly linked to (functional) immaturity of the cerebral vascular bed and nervous system and commonly encountered inflammation. The second part discusses repair of hemorrhagic- ischemic and post-inflammatory brain lesions as it is an increasingly important topic in newborn medicine. In the near future trials of trophic and (autologous or allogenic) cell-therapy in infants at risk of or demonstrating established PIVH and WMI will be started. The focus of these potential trials will be discussed

Pulmonary Effects of Neonatal Hydrocortisone Treatment in Ventilator-Dependent Preterm Infants

Background/Objective. Hydrocortisone, administered to ventilated preterm neonates to facilitate extubation, has no adverse long-term effects, but short-term pulmonary effects have not been described previously. In the present study, we analyzed effects of hydrocortisone on ventilator settings and FiO2 in ventilator-dependent preterm infants. Patients and Methods. Fifty-five preterm children were included in this retrospective cohort study. Hydrocortisone was administered at a postnatal age of > 7 days to treat chronic lung disease (CLD). Ventilator settings before and after hydrocortisone administration were recorded as well as FiO2 at 36 weeks' gestational age. Presence of cerebral palsy was assessed at a mean corrected age of 24.1 months. Results. Hydrocortisone administered at a median postnatal age of 14 days significantly reduced FiO2 from a median of 0.39 to 0.30, mean airway pressure (MAP) from a median of 10.0 cm H2O to 7.6 cm H2O, and PaCO2 from a median of 53.5 mmHg to 47 mmHg. Extubation was achieved in all patients. CLD at 36 weeks was present in 11 of the 52 patients (21.1%). None developed cerebral palsy. Conclusions. Hydrocortisone was effective in reducing the FiO2, MAP, and PaCO2 and facilitated extubation. Hydrocortisone was not associated with cerebral palsy

Detection of cerebral autoregulation by near-infrared spectroscopy in neonates: performance analysis of measurement methods

Cerebral Autoregulation, in clinical practice, is assessed by means of correlation or coherence analysis between mean arterial blood pressure (MABP) and cerebral blood flow (CBF). However, even though there is evidence linking cerebral autoregulation assessment with clinical outcome in preterm infants, available methods lack precision for clinical use. Classical methods, used for cerebral autoregulation, are influenced by the choice of parameters such as the length of the epoch under analysis and the choice of suitable frequency bands. The influence of these parameters, in the derived measurements for cerebral autoregulation, has not yet been evaluated. In this study, cerebral autoregulation was assessed using correlation, coherence, a modified version of coherence and transfer function gain, and phase. The influence of the extra-parameters on the final scores was evaluated by means of sensitivity analysis. The methods were applied to a database of 18 neonates with measurements of MABP and tissue oxygenation index (TOI). TOI reflects changes in CBF and was measured by means of near-infrared spectroscopy

Diagnostic and predictive value of Doppler ultrasound for evaluation of the brain circulation in preterm infants: a systematic review

INTRODUCTION: Very and extremely preterm infants frequently have brain injury-related long-term neurodevelopmental problems. Altered perfusion, for example, seen in the context of a hemodynamically significant patent ductus arteriosus (PDA), has been linked to injury of the immature brain. However, a direct relation with outcome has not been reviewed systematically. METHODS: A systematic review was conducted to provide an overview of the value of different cerebral arterial blood flow parameters assessed by Doppler ultrasound, in relation to brain injury, to predict long-term neurodevelopmental outcome in preterm infants. RESULTS: In total, 23 studies were included. Because of heterogeneity of studies, a meta-analysis of results was not possible. All included studies on resistance index (RI) showed significantly higher values in subjects with a hemodynamically significant PDA. However, absolute differences in RI values were small. Studies using Doppler parameters to predict brain injury and long-term neurodevelopmental outcome were inconsistent. DISCUSSION: There is no clear evidence to support the routine determination of RI or other Doppler parameters in the cerebral arteries to predict brain injury and long-term neurodevelopmental outcome in the preterm infant. However, there is evidence that elevated RI can point to the presence of a hemodynamically significant PDA

Effects of Antenatal Glucocorticoid Therapy on Hippocampal Histology of Preterm Infants

Objective: To investigate if antenatal glucocorticoid treatment has an effect on hippocampal histology of the human preterm newborn. Patients and Methods: Included were consecutive neonates with a gestational age between 24 and 32 weeks, who were born between 1991 to 2009, who had died within 4 days after delivery and underwent brain autopsy. Excluded were neonates with congenital malformations and neonates treated postnatally with glucocorticoids. The brains were routinely fixed, samples of the hippocampus were stained with haematoxylin and eosin and sections were examined for presence or absence of large and small neurons in regions of the hippocampus. Additional staining with GFAP, neurofilament and vimentin was performed to evaluate gliosis and myelination. The proliferation marker Ki67 was used to evaluate neuronal proliferation. Staining with acid fuchsin-thionin was performed to evaluate ischemic damage. Results: The hippocampi of ten neonates who had been treated with antenatal glucocorticoids showed a lower density of large neurons (p = 0.01) and neurons irrespective of size (p = 0.02) as compared to eleven neonates who had not been treated with glucocorticoids. No difference was found in density of small neurons, in myelination, gliosis, proliferation or ischemic damage. Conclusion: We found a significantly lower density of neurons in the hippocampus of neonates after antenata

Diaphragm and abdominal organ motion during radiotherapy:a comprehensive multicenter study in 189 children

Background: For accurate thoracic and abdominal radiotherapy, inter- and intrafractional geometrical uncertainties need to be considered to enable accurate margin sizes. We aim to quantify interfractional diaphragm and abdominal organ position variations, and intrafractional diaphragm motion in a large multicenter cohort of pediatric cancer patients (&lt; 18 years). We investigated the correlation of interfractional position variations and intrafractional motion with age, and with general anesthesia (GA). Methods: In 189 children (mean age 8.1; range 0.4–17.9 years) from six institutes, interfractional position variation of both hemidiaphragms, spleen, liver, left and right kidneys was quantified using a two-step registration. CBCTs were registered to the reference CT relative to the bony anatomy, followed by organ registration. We calculated the group mean, systematic and random errors (standard deviations Σ and σ, respectively) in cranial-caudal (CC), left-right and anterior-posterior directions. Intrafractional right hemidiaphragm motion was quantified using CBCTs on which the breathing amplitude, defined as the difference between end-inspiration and end-expiration peaks, was assessed (N = 79). We investigated correlations with age (Spearman’s ρ), and differences in motion between patients treated with and without GA (N = 75; all &lt; 5.5 years). Results: Interfractional group means were largest in CC direction and varied widely between patients, with largest variations in the right hemidiaphragm (range -13.0–17.5 mm). Interfractional group mean of the left kidney showed a borderline significant correlation with age (p = 0.047; ρ = 0.17). Intrafractional right hemidiaphragm motion in patients ≥ 5.5 years (mean 10.3 mm) was significantly larger compared to patients &lt; 5.5 years treated without GA (mean 8.3 mm) (p = 0.02), with smaller Σ and σ values. We found a significant correlation between breathing amplitude and age (p &lt; 0.001; ρ = 0.43). Interfractional right hemidiaphragm position variations were significantly smaller in patients &lt; 5.5 years treated with GA than without GA (p = 0.004), but intrafractional motion showed no significant difference. Conclusion: In this large multicenter cohort of children undergoing thoracic and abdominal radiotherapy, we found that interfractional position variation does not depend on age, but the use of GA in patients &lt; 5.5 years showed smaller systematic and random errors. Furthermore, our results showed that breathing amplitude increases with age. Moreover, variations between patients advocate the need for a patient-specific margin approach.</p

No neurodevelopmental benefit of cerebral oximetry in the first randomised trial (SafeBoosC II) in preterm infants during the first days of life

Aim: Cerebral hypoxia has been associated with neurodevelopmental impairment. We studied whether reducing cerebral hypoxia in extremely preterm infants during the first 72 hours of life affected neurological outcomes at two years of corrected age. Methods: In 2012‐2013, the phase II randomised Safeguarding the Brains of our smallest Children trial compared visible cerebral near‐infrared spectroscopy (NIRS) monitoring in an intervention group and blinded NIRS monitoring in a control group. Cerebral hy oxia was significantly reduced in the intervention group. We followed up 115 survivors from eight European centres at two years of corrected age, by conducting a medical examination and assessing their neurodevelopment with the Bayley Scales of Infant and Toddler Development, Second or Third Edition, and the parental Ages and Stages Questionnaire (ASQ). Results: There were no differences between the intervention (n = 65) and control (n = 50) groups with regard to the mean mental developmental index (89.6 ± 19.5 versus 88.4 ± 14.7, p = 0.77), ASQ score (215 ± 58 versus 213 ± 58, p = 0.88) and the number of children with moderate‐to‐severe neurodevelopmental impairment (10 versus six, p = 0.58). Conclusions: Cerebral NIRS monitoring was not associated with long‐term benefits or harm with regard to neurodevelopmental outcome at two years of corrected age