Fetal chronic hypoxia does not affect urinary presepsin levels in newborns at birth.

OBJECTIVES: Early sepsis detection and diagnosis still constitutes an open issue since the accuracy of standard-of care parameters is biased by a series of perinatal factors including hypoxia. Therefore, we aimed at investigating the effect of fetal chronic hypoxia insult on urine levels of a promising new marker of sepsis, namely presepsin (P-SEP). METHODS: We conducted a prospective case-control study in 22 cases of early-intrauterine growth restriction (E-IUGR) compared with 22 small-for-gestational-age (SGA) newborns and 66 healthy controls. P-SEP urine samples were collected over the first 72 h from birth. Blood culture and C-reactive protein (CRP) blood levels were measured in E-IUGR and SGA infants. Perinatal standard monitoring parameters and main outcomes were also recorded. RESULTS: No significant urinary P-SEP differences (p>0.05, for all) were observed among studied groups. Moreover, no significant correlations (p>0.05, for both) between urinary P-SEP and blood CRP levels in both E-IUGR and SGA groups (R=0.08; R=0.07, respectively) were observed. CONCLUSIONS: The present results showing the lack of influence of fetal chronic hypoxia on urinary P-SEP levels offer additional data to hypothesize the possible use of urinary P-SEP measurement in neonates in daily clinical practice. Further multicenter prospective data are needed, including infants with early-onset sepsis.

Elevated S100B urine levels predict seizures in infants complicated by perinatal asphyxia and undergoing therapeutic hypothermia.

OBJECTIVES: Seizures (SZ) are one of the main complications occurring in infants undergoing therapeutic hypothermia (TH) due to perinatal asphyxia (PA) and hypoxic ischemic encephalopathy (HIE). Phenobarbital (PB) is the first-line therapeutic strategy, although data on its potential side-effects need elucidation. We investigated whether: i) PB administration in PA-HIE TH-treated infants affects S100B urine levels, and ii) S100B could be a reliable early predictor of SZ. METHODS: We performed a prospective case-control study in 88 PA-HIE TH infants, complicated (n=44) or not (n=44) by SZ requiring PB treatment. S100B urine levels were measured at 11 predetermined monitoring time-points from first void up to 96-h from birth. Standard-of-care monitoring parameters were also recorded. RESULTS: S100B significantly increased in the first 24-h independently from HIE severity in the cases who later developed SZ and requested PB treatment. ROC curve analysis showed that S100B, as SZ predictor, at a cut-off of 2.78 µg/L achieved a sensitivity/specificity of 63 and 84 %, positive/negative predictive values of 83 and 64 %. CONCLUSIONS: The present results offer additional support to the usefulness of S100B as a trustable diagnostic tool in the clinical daily monitoring of therapeutic and pharmacological procedures in infants complicated by PA-HIE.

Effect of temperature on presepsin pre-analytical stability in biological fluids of preterm and term newborns.

OBJECTIVES: Thermostability is one of the pre-requisites for the reliability of analytes in clinical practice and biomedical research. Although presepsin represents a promising new biomarker for the early diagnosis of sepsis in newborns, data on its stability under different storage conditions are lacking. We aimed to investigate presepsin thermostability in blood, urine and saliva samples after thawing at 4 predetermined monitoring time-points in a cohort of preterm and term infants. METHODS: We conducted an observational study, where each case served as its own control, in 24 preterm and term infants. Blood, urine and saliva samples were stored at -80 °C for 18 months, and presepsin measured in different biological fluids at thawing (T0), 24 (T1), 48 (T2) and at 72 (T3) hours after thawing. RESULTS: No significant differences (p>0.05, for all) in presepsin levels were observed at T0-T3 in the different biological fluids. Furthermore, no differences at T0-T3 were observed in presepsin levels between blood and saliva fluids, whilst urine levels were significantly higher (p<0.05, for all) than blood and saliva at T0-T3. CONCLUSIONS: Results on presepsin pre-analytical thermo-stability in different biological fluids after long-term refrigeration support the reliability of this biomarker in the diagnosis and monitoring of perinatal sepsis.

Early predictors of abnormal MRI patterns in asphyxiated infants: S100B protein urine levels.

OBJECTIVES: The early detection and stratification of asphyxiated infants at higher risk for impaired neurodevelopment is challenging. S100B protein is a well-established biomarker of brain damage, but lacks conclusive validation according to the "gold standard" methodology for hypoxic-ischemic encephalopathy (HIE) prognostication, i.e. brain MRI. The aim of the present study was to investigate the predictive role of urinary S100B concentrations, assessed in a cohort of HIE infants receiving therapeutic hypothermia (TH), compared to brain MRI. METHODS: Assessment of urine S100B concentrations was performed by immunoluminometric assay at first void and at 4, 8, 12, 16, 20, 24, 48, 72, 96, 108 and 120-h after birth. Neurologic evaluation, routine laboratory parameters, amplitude-integrated electroencephalography, and cerebral ultrasound were performed according to standard protocols. Brain MRI was performed at 7-10 days of life. RESULTS: Overall, 74 HIE neonates receiving TH were included in the study. S100B correlated, already at first void, with the MRI patterns with higher concentrations in infants with the most severe MRI lesions. CONCLUSIONS: High S100B urine levels soon after birth constitute trustable predictors of brain injury as confirmed by MRI. Results support the reliability of S100B in clinical daily practice and open the way to its inclusion in the panel of parameters used for the selection of cases suitable for TH treatment.

Perinatal presepsin assessment: a new sepsis diagnostic tool?

Perinatal sepsis constitutes a medical emergency and is still one of the major causes of mortality and morbidity. The possibility of an early diagnosis of sepsis is still debated and controversial. In particular, clinical symptoms can be hidden by the association of sepsis with other perinatal diseases and/or by therapeutic strategies performed. In this context, there is evidence that the accuracy of standard of care diagnostic parameters (i.e. blood culture, C-reactive protein, procalcitonin) can be biased by additional confounding factors (gestational age, birth-weight, acute-chronic hypoxia). Therefore, the inclusion in clinical daily practice of new biomarkers of sepsis is of utmost importance. Of a panel of biomarkers, Presepsin (P-SEP) plays an important role in the development and response of the immune system and as an early marker of sepsis both in adult and pediatric patients. Therefore, in the present review we aim to offer an overview of the role of P-SEP in the early detection of perinatal sepsis as a trustworthy marker according to actual statements of official international institutions. Future perspectives regard the possibility of a longitudinal non-invasive biological fluids P-SEP assessment thus limiting the sample stress in high risk newborns.

Effect on splanchnic oxygenation of breast milk, fortified breast milk, and formula milk in preterm infants.

BACKGROUND: Enteral feeding induces mesenteric hemodynamic changes in preterm infants, which may vary according to the milk used. Our aim in this study was to evaluate changes of splanchnic regional oxygenation (rSO2S) measured by near-infrared spectroscopy (NIRS) in infants fed with mother's own milk (MOM), fortified human milk (FHM), or preterm formula (PTF). METHODS: Infants born at 25-31 weeks of gestational age (n = 54) received a bolus of MOM, FHM, or PTF. rSO2S and splanchnic fractional oxygen extraction ratio (FOES) were recorded 60 min before (T0), and 30 min (T1) and 120 min (T2) after the beginning of bolus feeding. RESULTS: In the MOM group, rSO2S and FOES did not change during the study period. In the FBM group, rSO2S decreased from T0 to T1 and increased from T1 to T2, while FOES changed in reverse. In the PTF group, rSO2S decreased from T0 to T1 and from T1 to T2, while FOES changed in reverse. CONCLUSIONS: Splanchnic oxygenation was not affected by MOM feeding, was transiently decreased by FBM feeding, and was persistently decreased by PTF. These results suggest that preterm infants who received PTF has higher splanchnic tissue oxygen extraction compared to those who received MOM or FBM. IMPACT: Human milk feeding is associated to a lower splanchnic energy expenditure than preterm formula feeding. Fortified human milk transiently increases splanchnic energy expenditure. Preterm formula should be used only in the absence of human milk.

Osteopathic Manipulation Treatment Improves Cerebro-splanchnic Oximetry in Late Preterm Infants.

Background: To evaluate the effectiveness/side-effects of osteopathic manipulation treatment (OMT) performed on the 7th post-natal day, on cerebro-splanchnic oximetry, tissue activation and hemodynamic redistribution in late preterm (LP) infants by using near infrared spectroscopy (NIRS). Methods: Observational pretest-test study consisting in a cohort of 18 LPs who received OMT on the 7th post-natal day. NIRS monitoring was performed at three different time-points: 30 min before (T0), (30 min during (T1) and 30 min after OMT (T2). We evaluated the effects of OMT on the following NIRS parameters: cerebral (c), splanchnic (s) regional oximetry (rSO2), cerebro-splanchnic fractional tissue oxygen extraction (FTOE) and hemodynamic redistribution (CSOR). Results: crSO2 and cFTOE significantly (P < 0.001) improved at T0-T2; srSO2 significantly (P < 0.001) decreased and sFTOE increased at T0-T1. Furthermore, srSO2 and sFTOE significantly improved at T1-T2. Finally, CSOR significantly (P < 0.05) increased at T0-T2. Conclusions: The present data show that OMT enhances cerebro-splanchnic oximetry, tissue activation and hemodynamic redistribution in the absence of any adverse clinical or laboratory pattern. The results indicate the usefulness of further randomized studies in wider populations comparing the effectiveness of OMT with standard rehabilitation programs.

Cerebral NIRS patterns in late preterm and very preterm infants becoming late preterm.

BACKGROUND: Near Infrared Spectroscopy (NIRS) has been proposed as a useful, noninvasive monitoring technique providing reliable information about central nervous system (CNS) oximetry and function. Recently, brain damage has been reconsidered as a dynamic process evolving over the weeks of gestation. We therefore investigated NIRS cerebral pattern differences between healthy late preterm infants (LPTo) and very preterm infants becoming late preterm (LPT). METHODS: We conducted an observational study in 40 healthy late preterm infants, matched for gestational age at monitoring, of whom 20 where LPTo and 20 LPT. Clinical, diagnostic and laboratory monitoring procedures and cerebral oximetry (crSO2) and function (cFTOE) were recorded on admission into the study. RESULTS: No significant differences (p > .05, for all) were found between groups regarding clinical, diagnostic or laboratory parameters. Higher crSO2 and lower cFTOE (p < .001, for both) were found in the LPTo group. CONCLUSIONS: Our results, showing impaired oximetry and function of CNS in LPT, offer additional support to NIRS parameters as a useful tool for longitudinal CNS monitoring of very preterm infants becoming LPT. Future studies correlating NIRS variables and long-term neurological outcome in LPT are needed to elucidate the concept of dynamic brain damage pathogenesis.

NIRS cerebral patterns in healthy late preterm and term infants are gender- and gestational age-dependent.

AIM: Near-infrared spectroscopy (NIRS) has been proposed to provide reliable information concerning brain oximetry and tissue activation level in the perinatal period. We aimed to investigate whether NIRS brain patterns in healthy preterm (PT) and term (T) infants were gender- and gestational age (GA)-dependent. METHODS: We conducted an observational study in 74 newborns, from consecutive singleton pregnancies, of whom 37 were born at term (male: n = 19 female: n = 18) and 37 (male: n = 18 female: n = 19) were PT. Cerebral oximetry (crSO2 ) and fractional tissue oxygen extraction (cFTOE), were recorded on the 5th day from birth. RESULTS: crSO2 was significantly higher and cFTOE lower (p < 0.001, for both) in the PT female than male group. At term, crSO2 was significantly higher and cFTOE lower (p < 0.001, for both) in males. crSO2 (male: R = 0.84, p < 0.001; female: R = 0.74, p < 0.001) and cFTOE (male: R = 0.72, p < 0.001; female: R = 0.72, p < 0.001) in male and female groups correlated positively with GA at recording. CONCLUSION: Different brain oximetry between males and females in PT a T infants, may suggest that in the perinatal period brain development is gender- and time-dependent. Data support the use of NIRS as a feasible tool for non-invasive cerebral monitoring.

Near-infrared spectroscopy is a promising noninvasive technique for monitoring the effects of feeding regimens on the cerebral and splanchnic regions.

AIM: The effects of different milk and, or, administration regimens on cerebro-splanchnic perfusion are still a matter of debate. We investigated the effects of the bolus administration of breast milk or formula on cerebro-splanchnic oximetry, function and perfusion, assessed by near-infrared spectroscopy (NIRS). METHODS: This observational study of 30 infants fed with breast (n = 15) or formula (n = 15) milk, and matched for gestational age and birth weight, was carried out in the neonatal intensive care unit of the C Arrigo Children's Hospital, Alessandria, Italy, a tertiary-level referral centre, from October 2015 to December 2016. NIRS monitoring parameters, such as cerebral and splanchnic oximetry, fraction of tissue oxygen extraction and the cerebral-splanchnic ratio, were recorded before, during and after feeding. RESULTS: Breast milk led to a significant increase in cerebro-splanchnic oximetry and tissue oxygen extraction (p < 0.001) during and after feeding, and the cerebro-splanchnic perfusion ratio was significantly higher (p < 0.001) in the breast than formula group. CONCLUSION: Our study results suggest that breast milk was better tolerated than formula, requiring lower energy expenditure and lower cerebro-splanchnic haemodynamic redistribution. The findings could prompt investigations using NIRS as a promising noninvasive tool for cerebral and splanchnic longitudinal monitoring during neonatal feeding.

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.