Francesco M. Risso

New markers of neonatal neurology

Hypoxia–ischemia (H–I) constitutes the main phenomenon responsible for brain–blood barrier permeability modifications leading to cerebral vascular auto-regulation loss in newborns. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular auto-regulation loss leading to cell death and tissue damage. Reperfusion could be critical since organ damage, particularly of the brain, may be amplified during this period. An exaggerated activation of vasoactive agents, of calcium mediated effects could be responsible for reperfusion injury (R-I), which, in turns, leads to cerebral hemorrhage and damage. These phenomena represent a common repertoire in newborns complicated by perinatal acute or chronic hypoxia treated by risky procedures such as mechanical ventilation, nitric oxide supplementation, brain cooling, and extracorporeal membrane oxygenation (ECMO). Despite accurate monitoring, the post-insult period is crucial, as clinical symptoms and standard monitoring parameters may be silent at a time when brain damage is already occurring and the therapeutic window for pharmacological intervention is limited. Therefore, the measurement of circulating biochemical markers of brain damage, such as vasoactive agents and nervous tissue peptides is eagerly awaited in clinical practice to detect high risk newborns. The present review is aimed at investigating the role of biochemical markers such as adrenomedullin, a vasoactive peptide; S100B, a calcium binding protein, activin A, a glycoprotein, in the cascade of events leading to I-R injury in newborns complicated by perinatal asphyxia.

Neurological Abnormalities in Full-Term Asphyxiated Newborns and Salivary S100B Testing: The “Cooperative Multitask against Brain Injury of Neonates” (CoMBINe) International Study

Background Perinatal asphyxia (PA) is a leading cause of mortality and morbidity in newborns: its prognosis depends both on the severity of the asphyxia and on the immediate resuscitation to restore oxygen supply and blood circulation. Therefore, we investigated whether measurement of S100B, a consolidated marker of brain injury, in salivary fluid of PA newborns may constitute a useful tool for the early detection of asphyxia-related brain injury. Methods We conducted a cross-sectional study in 292 full-term newborns admitted to our NICUs, of whom 48 suffered PA and 244 healthy controls admitted at our NICUs. Saliva S100B levels measurement longitudinally after birth; routine laboratory variables, neurological patterns, cerebral ultrasound and, magnetic resonance imaging were performed. The primary end-point was the presence of neurological abnormalities at 12-months after birth. Results S100B salivary levels were significantly (P<0.001) higher in newborns with PA than in normal infants. When asphyxiated infants were subdivided according to a good (Group A; n = 15) or poor (Group B; n = 33) neurological outcome at 12-months, S100B was significantly higher at all monitoring time-points in Group B than in Group A or controls (P<0.001, for all). A cut-off >3.25 MoM S100B achieved a sensitivity of 100% (CI5-95%: 89.3%-100%) and a specificity of 100% (CI5-95%: 98.6%-100%) as a single marker for predicting the occurrence of abnormal neurological outcome (area under the ROC curve: 1.000; CI5-95%: 0.987-1.0). Conclusions S100B protein measurement in saliva, soon after birth, is a useful tool to identify which asphyxiated infants are at risk of neurological sequelae.

Biomarkers of brain damage in preterm infants.

Objective: There is growing evidence on the usefulness of biomarkers in the early detection of preterm infants at risk for brain damage. However, among different tools Activin A, S100B protein and adrenomedullin assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more non-invasive techniques in order to fulfill the minimal handling in diagnostic and therapeutic strategy performance. Materials and methods: The concept of Unconventional Biological Fluid (UBF: urine and saliva) is becoming even stronger and regards the assessment in non-invasive biological fluids of biochemical markers involved in the cascade of events leading to brain damage. Results: Activin A, S100B protein and adrenomedullin in UBF were increased in preterm newborns developing brain damage and/or ominous outcome. Conclusions: The present manuscript offers an update on the usefulness of Activin A, S100B protein an adrenomedullin in UBF as brain damage markers. The findings open a new cue on the use of these markers in daily neonatal intensive care unit (NICU) activities.

Perinatal asphyxia: Kidney failure does not affect S100B urine concentrations

BACKGROUND S100B protein is a well-established marker of brain damage. Its importance in urine assessment is the convenience of a collection and sampling procedure that can be repeated without risk for the newborn. Since S100B is mainly eliminated by the kidneys and perinatal asphyxia (PA) is often associated with kidney failure we investigated whether S100B release might be kidney-mediated, thereby modifying the proteins reliability as a brain-damage marker. METHODS We examined a cohort of healthy (n=432) and asphyxiated newborns (n=32) in whom kidney function parameters (blood urea and creatinine concentrations and urine gravity) and urine S100B concentrations were assessed in the first hours after birth. Data were analyzed by multiple logistic regression analysis with S100B as independent variable among a variety of clinical and laboratory monitoring parameters. RESULTS S100B urine concentrations were significantly higher (P<0.01) in PA newborns than controls. No significant correlations (P>0.05, for all) between total urine S100B levels and kidney function parameters such as creatinine (r=0.03), urea (r=0.04) and urine gravity (r=0.06) were found. Multiple logistic regression analysis of a series of clinical and laboratory monitoring parameters (odds ratio at sampling: 9.47) with S100B as independent variable showed a positive significant correlation only between S100B levels (P<0.001) and the occurrence of PA. CONCLUSION The present study shows that altered kidney function is not an adverse and/or confounding factor in urine S100B assessment and marks a new step towards the introduction of longitudinal monitoring of brain constituents in clinical practice.

S100B urine concentrations in late preterm infants are gestational age and gender dependent

BACKGROUND Late preterm deliveries (LP, between 34 and 36wks), have considerably increased in the last decades. About 20-25% of LP infants who require intensive care and morbidity on public health are of great magnitude. Therefore, we aimed at offering a reference curve in LP period of a well-established neurotrophic and brain damage marker namely S100B protein. METHODS We collected, between December 2009 and March 2012, urine samples, at first void (within 6-hours from birth) for S100B assessment, in 277 healthy LP infants consecutively admitted to our units. Standard clinical and laboratory monitoring parameters were also recorded. S100B was measured by using a commercially available immunoluminometric assay. RESULTS S100B pattern in LP infants was characterized by a slight decrease in proteins concentration from 34 to 35wks. From 35wks onwards S100B started to increase reaching a significant difference (P=0.008) at 36wks. When corrected for gender, significantly higher (P<0.01, for all) S100B concentrations in female were observed from 34 to 36wks. Polynomial type-1 regression analysis showed a significant correlation (R=-0.05; P<0.001) between gestational age and S100B in LP infants considering either the whole study population or when corrected for gender. CONCLUSIONS S100B in LP infants is gestational age and gender dependent. The present reference curve, for S100B in LP period, offers additional support to proteins neurotrophic role and suggests that gestational age and gender have to be taken into due account, whenever S100B is measured, in order to avoid bias factors.

Urine S100 BB and A1B dimers are valuable predictors of adverse outcome in full-term asphyxiated infants

To investigate whether S100A1B and BB dimers are predictors of early perinatal death in newborns with perinatal asphyxia (PA).

Antenatal glucocorticoid treatment affects preterm infants' S100B urine concentration in a dose-dependent manner

BACKGROUND Maternal glucocorticoid (GC) treatment is widely used to prevent lung immaturity in preterm infants. There is growing evidence that GCs may be detrimental to the Central Nervous System (CNS). We investigated whether antenatal GC administration affects CNS function in a dose-dependent manner by measuring urine concentrations of a well-established brain damage marker, S100B. METHODS We conducted a case-control-study in 70 preterm infants (1 GC vs 1 control) whose mothers received a complete GC-course (GC2, n=16), half-course (GC1, n=19), and controls (n=35). At four predetermined time-points, in the first 72 h from birth, we assessed S100B urine concentrations, using a commercially available immunoluminometric assay (Lia-mat Sangtec 100, AB Sangtec Medical, Bromma, Sweden). Data were correlated with primary neonatal outcomes (incidence of respiratory distress syndrome, length of ventilatory support and hospital stay, incidence of intraventricular hemorrhage, adverse 7th day neurological follow-up and neonatal death). RESULTS S100B in GC2 group at all monitoring time-points was significantly lower (P<0.01) than controls and GC1 group, while no differences (P>0.05) were evident between controls and GC1 group. No significant differences (P>0.05) were shown in primary outcomes between half or complete GC-course treated groups. CONCLUSION S100B levels of infants antenatally treated with GCs differed in a dose-dependent manner. Data on primary outcomes suggest that lowering antenatal GC-course may be less detrimental for brain without affecting lung maturation. Further clinical trials are needed to elucidate the low GC-course issue.

Activity of linezolid and daptomycin against methicillin-resistant coagulase-negative staphylococci with increased MIC for vancomycin isolated from blood cultures in pediatric patients

Abstract We evaluated minimal inhibitory concentration (MIC) for vancomycin, daptomycin, and linezolid in methicillin-resistant coagulase-negative staphylococci (MR-CoNS). Minimal inhibitory concentration of 2–4 mg/l for vancomycin was observed in 16% of strains, and among them 19% had MIC at breakpoint for daptomycin or linezolid. Among strains completely susceptible to vancomycin, 16% had MIC at breakpoint for daptomycin and 11% had for linezolid. This large proportion of pathogens with MIC around the breakpoint suggests a possible risk of treatment failure with these drugs. This phenomenon is worth further and constant monitoring.

Invasive mould infections in newborns and children

Invasive mould infections represent important complications of different pediatric conditions. Epidemiology and clinical features vary according to the type of underlying conditions that determine the risk of invasive mycosis. No pediatric study has specifically evaluated the efficacy of prophylaxis or therapy invasive moulds infections, while pediatric dosages for the treatment of invasive aspergillosis are available for drugs that produced positive results in clinical trials undertaken in adults.

Preterm and term newborn: primary investigations.

The present overview is aimed at reporting the standard primary investigations that are mandatory in preterm and term newborns at admission to neonatal unit in the first hours after birth. Herein, the main neonatal screening tests for early detection of metabolic diseases are described as well as laboratory standard procedures (glycaemia, bilirubin, blood gas, infectious diseases analyses) monitoring parameters (vital signs recordings, blood and transcutaneous gas assessment, blood pressure recordings) and ultrasound pattern (cranial and cardiac).