Perinatal asphyxia leads to acute kidney damage and increased renal susceptibility in adulthood.

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 minutes) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat-shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (KIM-1, NGAL), hypoxic- and heat shock factors (HIF-1α, HSF-1, HSP-27), pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α, MCP-1), and fibrotic markers (TGF-ß, CTGF, Fibronectin) promptly after PA. Moreover, a machine learning model was identified through Random Forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic-, heat-shock-, pro-inflammatory-, and pro-fibrotic response after renal IRI compared to controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. Additionally, the parameters identified through Random Forest analysis provide a robust foundation for future biomarker research in the context of PA.

Quantitative Detection of Thyroid-Stimulating Hormone in Patient Samples with a Nanomechanical Single-Antibody Spectro-Immunoassay.

Functional disorders of the thyroid remain a global challenge and have profound impacts on human health. Serving as the barometer for thyroid function, thyroid-stimulating hormone (TSH) is considered the single most useful test of thyroid function. However, the prevailing TSH immunoassays rely on two types of antibodies in a sandwich format. The requirement of repeated incubation and washing further complicates the issue, making it unable to meet the requirements of the shifting public health landscape that demands rapid, sensitive, and low-cost TSH tests. Herein, a systematic study is performed to investigate the clinical translational potential of a single antibody-based biosensing platform for the TSH test. The biosensing platform leverages Raman spectral variations induced by the interaction between a TSH antigen and a Raman molecule-conjugated TSH antibody. In conjunction with machine learning, it allows TSH concentrations in various patient samples to be predicted with high accuracy and precision, which is robust against substrate-to-substrate, intra-substrate, and day-to-day variations. It is envisioned that the simplicity and generalizability of this single-antibody immunoassay coupled with the demonstrated performance in patient samples pave the way for it to be widely applied in clinical settings for low-cost detection of hormones, other molecular biomarkers, DNA, RNA, and pathogens.

Cesarean delivery is associated with lower neonatal mortality among breech pregnancies - a systematic review and meta-analysis of preterm deliveries ≤32 weeks of gestation.

OBJECTIVE: To investigate the association between actual and planned modes of delivery, neonatal mortality, and short-term outcomes among preterm pregnancies ≤32 weeks of gestation. DATA SOURCES: A systematic literature search was conducted in three main databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 16, 2022. The protocol was registered in advance in the International Prospective Register of Systematic Reviews (CRD42022377870). STUDY ELIGIBILITY CRITERIA: Eligible studies examined pregnancies ≤ 32nd gestational week. All infants received active care, and the outcomes were reported separately by different modes of delivery. Singleton and twin pregnancies at vertex and breech presentations were included. Studies that included pregnancies complicated with preeclampsia and abruptio placentae were excluded. Primary outcomes were neonatal mortality and intraventricular hemorrhage. STUDY APPRAISAL AND SYNTHESIS METHODS: Articles were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random effects model-based odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. ROBINS-I was used to assess the risk of bias. RESULTS: A total of nineteen observational studies were included involving a total of 16,042 preterm infants in this systematic review and meta-analysis. Actual cesarean delivery improves survival (odds ratio, 0.62; 95% confidence interval, 0.42 to 0.9) and decreases the incidence of intraventricular hemorrhage (odds ratio, 0.70; confidence interval, 0.57 to 0.85) compared to vaginal delivery. Planned cesarean delivery does not improve the survival of very and extremely preterm infants compared to vaginal delivery (odds ratio, 0.87; 95% confidence interval, 0.53 to 1.44). Subset analysis found significantly lower odds of death for singleton breech preterm deliveries born by both planned (odds ratio, 0.56; 95% confidence interval, 0.32 to 0.98) and actual (odds ratio, 0.34; 95% confidence interval, 0.13 to 0.88) cesarean delivery. CONCLUSION: Cesarean delivery should be the mode of delivery for preterm ≤32 weeks of gestation breech births due to the higher mortality in preterm infants born via vaginal delivery.

The predictive value of MRI scores for neurodevelopmental outcome in infants with neonatal encephalopathy.

BACKGROUND: MRI scoring systems are utilized to quantify brain injury and predict outcome in infants with neonatal encephalopathy (NE). Our aim was to evaluate the predictive accuracy of total scores, white matter (WM) and grey matter (GM) subscores of Barkovich and Weeke scoring systems for neurodevelopmental outcome at 2 years of age in infants receiving therapeutic hypothermia for NE. METHODS: Data of 162 infants were analyzed in this retrospective cohort study. DeLong tests were used to compare areas under the curve of corresponding items of the two scoring systems. LASSO logistic regression was carried out to evaluate the association between MRI scores and adverse composite (death or severe disabilities), motor and cognitive outcomes (Bayley developmental index <70). RESULTS: Weeke scores predicted each outcome measure with greater accuracy than the corresponding items of Barkovich system (DeLong tests p < 0.03). Total scores, GM and cerebellum involvement were associated with increased odds for adverse outcomes, in contrast to WM injury, after adjustment to 5' Apgar score, first postnatal lactate and aEEG normalization within 48 h. CONCLUSION: A more detailed scoring system had better predictive value for adverse outcome. GM injury graded on both scoring systems was an independent predictor of each outcome measure. IMPACT STATEMENTS: A more detailed MRI scoring system had a better predictive value for motor, cognitive and composite outcomes. While hypoxic-ischemic brain injuries in the deep grey matter and cerebellum were predictive of adverse outcome, white matter injury including cortical involvement was not associated with any of the outcome measures at 2 years of age. Structured MRI evaluation based on validated scores may aid future clinical research, as well as inform parents and caregivers to optimize care beyond the neonatal period.

Airway management may influence postoperative ventilation need in preterm infants after laser eye treatment.

BACKGROUND: Retinopathy of prematurity is treated with laser photocoagulation under general anaesthesia with intubation using endotracheal tube (ETT), which carries a risk for postoperative mechanical ventilation (MV). Laryngeal mask airway (LMA) may provide a safe alternative. We assessed the need for postoperative MV in preterm infants who received LMA versus ETT. METHODS: In this single-centre, retrospective cohort study, preterm infants who underwent laser photocoagulation between 2014-2021 were enroled. For airway management, patients received either LMA (n = 224) or ETT (n = 47). The outcome was the rate of postoperative MV. RESULTS: Patients' age were 37 [35;39] weeks of postmenstrual age, median bodyweight of Group LMA was higher than Group ETT's (2110 [1800;2780] g versus 1350 [1230;1610] g, respectively, p < 0.0001). After laser photocoagulation, 8% of Group LMA and 74% of Group ETT left the operating theatre requiring MV. Multiple logistic regression revealed that the use of LMA and every 100 g increase in bodyweight significantly decreased the odds of mechanical ventilation (OR 0.21 [95% CI 0.07-0.60], and 0.73 [95% CI 0.63-0.84], respectively). Propensity score matching confirmed that LMA decreased the odds of postoperative MV (OR 0.30 [95% CI 0.11-0.70]). CONCLUSION: The use of LMA is associated with a reduced need for postoperative MV. IMPACT: Using laryngeal mask airway instead of endotracheal tube for airway management in preterm infants undergoing general anaesthesia for laser photocoagulation for treating retinopathy of prematurity could significantly decrease the postoperative need for mechanical ventilation. According to our current understanding, this has been the largest study investigating the effect of laryngeal mask airway during general anaesthesia in preterm infants. Our study suggests that the use of laryngeal mask airway is a viable alternative to intubation in the vulnerable population of preterm infants in need of laser treatment.

Higher parental education was associated with good cognitive outcomes in infants with hypoxic-ischaemic encephalopathy.

AIM: Predicting neurodevelopmental outcomes in hypoxic-ischaemic encephalopathy (HIE) remains imprecise, despite advanced imaging and neurophysiological tests. We explored the predictive value of socio-economic status (SES). METHODS: The cohort comprised 93 infants (59% male) with HIE, who had received therapeutic hypothermia. Patients underwent magnetic resonance imaging, and brain injuries were quantified using the Barkovich scoring system. Family SES was self-reported using a questionnaire. Adverse outcomes were defined as mild to severely delayed development with a score of ≤85 in any domain at 2 years of age, based on the Bayley Scales of Infant Development, Second Edition. Data are presented as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Multiple regression modelling revealed that higher parental education was strongly associated with good cognitive development, when adjusted for gestational age, serum lactate and brain injuries (OR 2.20, 95% CI 1.16-4.36). The effect size of parental education (ß = 0.786) was higher than one score for any brain injury using the Barkovich scoring system (ß = -0.356). The literacy environment had a significant effect on cognitive development in the 21 infants who had brain injuries (OR 40, 95% CI 3.70-1352). CONCLUSION: Parental education and the literacy environment influenced cognitive outcomes in patients with HIE.

The histologic fetal inflammatory response and neonatal outcomes: systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate the prognostic role of concomitant histological fetal inflammatory response with chorioamnionitis on neonatal outcomes through a systematic review and meta-analysis of existing literature. DATA SOURCES: The primary search was conducted on October 17, 2021, and it was updated on May 26, 2023, across 4 separate databases (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Scopus) without using any filters. STUDY ELIGIBILITY CRITERIA: Observational studies reporting obstetrical and neonatal outcomes of infant-mother dyads with histological chorioamnionitis and histological fetal inflammatory response vs infant-mother dyads with histological chorioamnionitis alone were eligible. Studies that enrolled only preterm neonates, studies on neonates born before 37 weeks of gestation, or studies on neonates with very low birthweight (birthweight <1500 g) were included. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42021283448). METHODS: The records were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random-effect model-based pooled odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes. RESULTS: Overall, 50 studies were identified. A quantitative analysis of 14 outcomes was performed. Subgroup analysis using the mean gestational age of the studies was performed, and a cutoff of 28 weeks of gestation was implemented. Among neonates with lower gestational ages, early-onset sepsis (pooled odds ratio, 2.23; 95% confidence interval, 1.76-2.84) and bronchopulmonary dysplasia (pooled odds ratio, 1.30; 95% confidence interval, 1.02-1.66) were associated with histological fetal inflammatory response. Our analysis showed that preterm neonates with a concomitant histological fetal inflammatory response are more likely to develop intraventricular hemorrhage (pooled odds ratio, 1.54; 95% confidence interval, 1.18-2.02) and retinopathy of prematurity (pooled odds ratio, 1.37; 95% confidence interval, 1.03-1.82). The odds of clinical chorioamnionitis were almost 3-fold higher among infant-mother dyads with histological fetal inflammatory response than among infant-mother dyads with histological chorioamnionitis alone (pooled odds ratio, 2.99; 95% confidence interval, 1.96-4.55). CONCLUSION: This study investigated multiple neonatal outcomes and found association in the case of 4 major morbidities: early-onset sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity.

The Alterations of Serum N-glycome in Response to SARS-CoV-2 Vaccination.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global concern since its outbreak in 2019, with one of the main solutions being vaccination. Altered glycosylation has been described in patients after SARS-CoV-2 infection, while the effect of vaccination on serum glycoproteins remained unexplored. In this study, total serum glycosylation was analyzed in patients after SARS-CoV-2 infection and/or mRNA vaccination in order to identify potential glycosylation-based alterations. Enzyme-linked immunosorbent assay was applied to identify post-COVID-19 and post-Vaccinated patients and rule out potential outliers. Serum samples were deglycosylated by PNGase F digestion, and the released glycans were fluorescently derivatized using procainamide labeling. Solid-phase extraction was used to purify the labeled glycans followed by the analysis of hydrophilic-interaction liquid chromatography with fluorescence and mass-spectrometric detection. Alterations of serum N-glycome in response to SARS-CoV-2 infection and mRNA vaccination were revealed by linear discriminant analysis.

A Dual-Modal Single-Antibody Plasmonic Spectro-Immunoassay for Detection of Small Molecules.

Small molecules play a pivotal role in regulating physiological processes and serve as biomarkers to uncover pathological conditions and the effects of therapeutic treatments. However, it remains a significant challenge to detect small molecules given the size as compared to macromolecules. Recently, the newly emerging plasmonic immunoassays based on surface-enhanced Raman scattering (SERS) offer great promise to deliver extraordinary sensitivity. Nevertheless, they are limited by the intrinsic SERS intensity fluctuations associated with the SERS uncertainty principle. The single transducer that relies on the intensity change is also prone to false signals. Additionally, the prevailing sandwich immunoassay format proves less effective towards detecting small molecules. To circumvent these critical issues, a dual-modal single-antibody approach that synergizes both the intensity and shift of the peak-based immunoassay with Raman enhancement, coined as the INSPIRE assay, is developed for small molecules detection. With two independent transduction mechanisms, it allows better prediction of analyte concentration and attenuation of signal artifacts, providing a new and robust strategy for molecular analysis. With a proof-of-concept demonstration for detection of free T4 and testosterone in serum matrix, the authors envision that the INSPIRE assay could be expanded for a wide spectrum of applications in biomedical diagnosis, discovery of new biopharmaceuticals, food safety, and environmental monitoring.

Leveraging Nanomechanical Perturbations in Raman Spectro-Immunoassays to Design a Versatile Serum Biomarker Detection Platform.

While immunoassays are pivotal to medical diagnosis and bioanalytical chemistry, the current landscape of public health has catalyzed an important shift in the requirements of immunoassays that demand innovative solutions. For example, rapid, label-free, and low-cost screening of a given analyte is required to inform the best countermeasures to combat infectious diseases in a timely manner. Yet, the current design of immunoassays cannot accommodate such requirements as constraint by accumulative challenges, such as repeated incubation and washing, and the need of two types of antibodies in the sandwich format. To provide a potential solution, herein, a plasmonic Raman immunoassay with single-antibody, multivariate regression, and shift-of-peak strategies, coined as the PRISM assay, for serum biomarkers detection, is reported. The PRISM assay relies on Raman reporter-antibody conjugates to capture analytes on a plasmonic substrate. The ensuing nanomechanical perturbations to vibration of Raman reporters induce subtle but characteristic spectral changes that encode rich information related to the captured analytes. By fusing Raman spectroscopy and chemometric analysis, both Raman frequency shift- and multivariate regression models for sensitive detection of biomarkers are developed. The PRISM assay is expected to find a wide range of applications in clinical diagnosis, food safety surveillance, and environmental monitoring.

Longitudinal Analysis of Amplitude-Integrated Electroencephalography for Outcome Prediction in Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To investigate the prognostic accuracy of longitudinal analysis of amplitude-integrated electroencephalography (aEEG) background activity to predict long-term neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: This single-center observational study included 149 neonates for derivation and 55 neonates for validation with moderate-severe HIE and of gestational age ≥35 weeks at a tertiary neonatal intensive care unit. Single-channel aEEG background pattern, sleep-wake cycling, and seizure activity were monitored over 84 hours during therapeutic hypothermia and rewarming, then scored for each 6-hour interval. Neurodevelopmental outcome was assessed using the Bayley Scales of Infant Development, Second Edition. Favorable outcome was defined as having both a Mental Development Index (MDI) score and Psychomotor Development Index (PDI) score ≥70, and adverse outcome was defined as either an MDI or a PDI <70 or death. Regression modeling for longitudinal analysis of repeatedly measured data was applied, and area under the receiver operating characteristic curve (AUC) was calculated. RESULTS: Longitudinal aEEG background analysis combined with sleep-wake cycling score had excellent predictive value (AUC, 0.90; 95% CI, 0.85-0.95), better than single aEEG scores at any individual time point. The model performed well in the independent validation cohort (AUC, 0.87; 95% CI, 0.62-1.00). The reclassification rate of this model compared with the conventional analysis of aEEG background at 48 hours was 18% (24 patients); 14% (18 patients) were reclassified correctly. Our results were used to develop a user-friendly online outcome prediction tool. CONCLUSIONS: Longitudinal analysis of aEEG background activity and sleep-wake cycling is a valuable and accurate prognostic tool.

Predictive performance and metabolite dynamics of proton MR spectroscopy in neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Prognostic value of proton MR spectroscopy (H-MRS) in hypoxic-ischemic encephalopathy (HIE) is acknowledged; however, effects of gestational age (GA) and postnatal age (PA) on prediction and metabolite levels are unknown. METHODS: One hundred and sixty-nine newborns with moderate-to-severe HIE were studied, having ≥1 H-MRS scan during postnatal days 0-14 and known neurodevelopmental outcome (Bayley-II score/cerebral palsy/death). Initial scans were categorized by PA (day 1-3/4-6/≥7), and metabolite ratios were compared by predictive value. Metabolite dynamics were assessed in a total of 214 scans performed in the study population, using regression modeling, with predictors GA, PA, and outcome. RESULTS: N-acetyl-aspartate (NAA)/creatine (Cr) and myo-inositol (mI)/NAA height ratios were consistently associated with outcome throughout the first 14 days, with the highest predictive value in the late (≥7 days) period (AUC = 0.963 and 0.816, respectively). Neither GA nor PA had an overall effect on these metabolite ratios, which showed strongest association with outcome (p < 0.001). Assessed separately in patients with good outcome, GA became a significant covariate for metabolite ratios (p = 0.0058 and 0.0002, respectively). However, this association disappeared in the poor outcome group. CONCLUSIONS: In HIE, NAA/Cr and mI/NAA give most accurate outcome prediction throughout postnatal days 0-14. GA only affected metabolite levels in the good outcome group. IMPACT: Proton MR spectroscopy metabolite ratios N-acetyl-aspartate/creatine and myo-inositol/N-acetyl-aspartate have persistently high predictive value throughout postnatal days 0-14 in newborns with hypoxic-ischemic encephalopathy, with the highest predictive power between postnatal days 7 and 14. Overall, neither metabolite ratio was affected by gestational age nor by postnatal age, while they showed the strongest association with neurological outcome. However, in newborns facing good outcome, metabolite ratios were associated with gestational age, whereas in cases facing poor outcome, this association disappeared. Proton MR spectroscopy provides valuable prognostic information in neonatal hypoxic-ischemic encephalopathy throughout the first 2 weeks of life, irrespective of the timing of MR scan.

Universal newborn hearing screening with automated auditory brainstem response (AABR) in Hungary: 5-year experience in diagnostics and influence on the early intervention.

PURPOSE: In 2015 a new regulation and guidelines for the universal newborn hearing screening by AABR measurement have been implemented in Hungary. The aim of our study was to analyse (1) the past 5 years of data from our diagnostic centre about the incidence and types of congenital hearing losses, and (2) the first experiences with the National Newborn Hearing Screening Registry, started in 2019, and (3) the influence of the screening on the pediatric cochlear implant program. METHODS: 1269 children referred to our diagnostic centre between 2017 and 2021 were investigated. A third AABR measurement and full audiological evaluation were performed. Furthermore, one-year period data of the screening registry, and the number of implanted children at or under the age of 3 were analysed using the national databases. RESULTS: Altogether 276 newborns (22% of the referred cases after the two-stage screening) had hearing loss, 134 (49%) out of them was conductive origin, almost twice frequent in male as in female. Permanent sensorineural hearing impairment was found in 142 (51%), 58 (40%) of them had bilateral, severe to profound hearing loss, occurring more frequently in male as in female. The national digital registration of the screening data within 12 months concerned 68%. The number of early cochlear implantation in one year increased from 1 to 23 children in the past 15 years. CONCLUSION: A third AABR after the two-stage screening increased the efficiency and filtered the 78% false-positive cases. The audiological diagnostics verified and typed the hearing losses ensuring the early intervention.

Plexcitonic Quasi-Bound States in the Continuum.

Enhancing light-matter interactions is fundamental to the advancement of nanophotonics and optoelectronics. Yet, light diffraction on dielectric platforms and energy loss on plasmonic metallic systems present an undesirable trade-off between coherent energy exchange and incoherent energy damping. Through judicious structural design, both light confinement and energy loss issues could be potentially and simultaneously addressed by creating bound states in the continuum (BICs) where light is ideally decoupled from the radiative continuum. Herein, the authors present a general framework based on the two-coupled resonances to first conceptualize and then numerically demonstrate a type of quasi-BICs that can be achieved through the interference between two bare resonance modes and is characterized by the considerably narrowed spectral line shape even on lossy metallic nanostructures. The ubiquity of the proposed framework further allows the paradigm to be extended for the realization of plexcitonic quasi-BICs on the same metallic systems. Owing to the topological nature, both plasmonic and plexcitonic quasi-BICs display strong mode robustness against parameters variation, thereby providing an attractive platform to unlock the potential of the coupled plasmon-exciton systems for manipulation of the photophysical properties of condensed phases.

Time varied illumination laser speckle contrast imaging.

Laser speckle contrast imaging is a technique to determine blood flow rate with a limitation of low dynamic range. In this Letter, we introduce a varied illumination speckle contrast imaging method. It utilizes varying illumination during exposure to customize the correlation time (flow rate) to speckle contrast relation. The method can cover an order of magnitude larger range flow rate in a single exposure compared to constant illumination methods. The proposed method enables high dynamic range flow rate imaging, which is advantageous in studying larger vessels and small arteries. We demonstrate the theory by simulations and ex vivo and in vivo measurements.

Cerebral oxygenation in preterm infants during maternal singing combined with skin-to-skin care.

BACKGROUND: Our aim was to investigate the effect of music therapy in combination with skin-to-skin care (SSC) on regional cerebral oxygenation (rSO2) measured with near-infrared spectroscopy (NIRS) in premature infants and to study physiological stability during the interventions. METHODS: This was a prospective single-center observational cohort study conducted in a tertiary neonatal intensive care unit. The study consisted of four phases: (1) baseline measurements in an incubator for 30 min; (2) quiet SSC for 30 min (SSC-Pre); (3) SSC with live maternal singing accompanied by live guitar music for 20 min (SSC-Music); (4) final quiet SSC for another 30 min (SSC-Post). RESULTS: The primary outcome measure of mean rSO2 for the 31 preterm infants analyzed showed a significant increase from baseline during SSC-Music (76.87% vs 77.74%, p = 0.04) and SSC-Post (76.87% vs 78.0%, p = 0.03) phases. There were no significant changes observed in heart rate (HR), peripheral oxygen saturation (SpO2), and cerebral fractional tissue oxygen extraction (cFTOE). The coefficient of variation (CV) of rSO2 and SpO2 decreased during each intervention phase. CONCLUSION: Combining music therapy with SSC appears to be safe in preterm neonates. The impact of the small increase in rSO2 and reduced variability of SpO2 and rSO2 warrants further investigation. IMPACT: Music therapy combined with skin-to-skin care (SSC) is safe in clinically stable premature infants and could be encouraged as part of developmental care. This is the first report where near-infrared spectroscopy (NIRS) was used to detect the simultaneous effect of music therapy and SSC on cerebral rSO2 in preterm infants. Music therapy with SSC caused a modest increase in rSO2 and decreased the coefficient of variation of rSO2 and peripheral oxygen saturation (SpO2), which suggest short-term benefits for preterm infants.

Neonatal encephalopathy therapy optimization for better neuroprotection with inhalation of CO2: the HENRIC feasibility and safety trial.

BACKGROUND: There is an association between hypocapnia and adverse neurodevelopmental outcome in infants with neonatal encephalopathy (NE). Our aim was to test the safety and feasibility of 5% CO2 and 95% air inhalation to correct hypocapnia in mechanically ventilated infants with NE undergoing therapeutic hypothermia. METHODS: Ten infants were assigned to this open-label, single-center trial. The gas mixture of 5% CO2 and 95% air was administered through patient circuits if the temperature-corrected PCO2 ≤40 mm Hg. The CO2 inhalation was continued for 12 h or was stopped earlier if the base deficit (BD) level decreased <5 mmol/L. Follow-up was performed using Bayley Scales of Infant Development II. RESULTS: The patients spent a median 95.1% (range 44.6-98.5%) of time in the desired PCO2 range (40-60 mm Hg) during the inhalation. All PCO2 values were >40 mm Hg, the lower value of the target range. Regression modeling revealed that BD and lactate had a tendency to decrease during the intervention (by 0.61 and 0.55 mmol/L/h, respectively), whereas pH remained stable. The rate of moderate disabilities and normal outcome was 50%. CONCLUSIONS: Our results suggest that inhaled 5% CO2 administration is a feasible and safe intervention for correcting hypocapnia.

A Randomized Controlled Study of Low-Dose Hydrocortisone Versus Placebo in Dopamine-Treated Hypotensive Neonates Undergoing Hypothermia Treatment for Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To investigate whether hydrocortisone supplementation increases blood pressure and decreases inotrope requirements compared with placebo in cooled, asphyxiated neonates with volume-resistant hypotension. STUDY DESIGN: A double-blind, randomized, placebo-controlled clinical trial was conducted in a Level III neonatal intensive care unit in 2016-2017. Thirty-five asphyxiated neonates with volume-resistant hypotension (defined as a mean arterial pressure [MAP] < gestational age in weeks) were randomly assigned to receive 0.5 mg/kg/6 hours of hydrocortisone or placebo in addition to standard dopamine treatment during hypothermia. RESULTS: More patients reached the target of at least 5-mm Hg increment of MAP in 2 hours after randomization in the hydrocortisone group, compared with the placebo group (94% vs 58%, P = .02, intention-to-treat analysis). The duration of cardiovascular support (P = .001) as well as cumulative (P < .001) and peak inotrope dosage (P < .001) were lower in the hydrocortisone group. In a per-protocol analysis, regression modeling predicted that a 4-mm Hg increase in MAP in response to hydrocortisone treatment was comparable with the effect of 15 µg/kg/min of dopamine in this patient population. Serum cortisol concentrations were low before randomization in both the hydrocortisone and placebo groups (median 3.5 and 3.3 µg/dL, P = .87; respectively), suggesting inappropriate adrenal function. Short-term clinical outcomes were similar in the 2 groups. CONCLUSIONS: Hydrocortisone administration was effective in raising the blood pressure and decreasing inotrope requirement in asphyxiated neonates with volume-resistant hypotension during hypothermia treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02700828.

Neurodevelopmental effect of intracranial hemorrhage observed in hypoxic ischemic brain injury in hypothermia-treated asphyxiated neonates - an MRI study.

BACKGROUND: Identification of early signs of hypoxic ischemic encephalopathy (HIE) with magnetic resonance imaging (MRI) has proven of prognostic significance. Yet, the importance of intracranial hemorrhage (ICH), being present concomitantly had not been investigated yet, despite the known influence of hypothermia on hemostasis. We aimed to determine whether presence of ICH on MRI alongside the signs of HIE have an impact on prognosis in neonates with the clinical diagnosis of HIE. METHODS: A retrospective study of consecutively sampled 108 asphyxiated term infants admitted to a tertiary neonatal intensive care unit (between 2007 and 2016), treated with whole body hypothermia and having brain MRI within 1 week of life was conducted. Presence or absence of HIE signs on MRI (basal ganglia-thalamus, watershed pattern and total brain injury) and on MR spectroscopy (lactate peak with decreased normal metabolites measured by Lac/NAA ratio) and/or of the five major types of ICH were recorded. Neurodevelopmental outcome was measured with Bayley Scales of Infant Development-II (BSID-II) test. Death or abnormal neurodevelopment (BSID-II score < 85) was defined as poor outcome in Chi-square test. Multivariate logistic regression analysis was performed on survivors. RESULTS: MRI and MR-spectroscopy (MRS) signs of HIE were present in 72% (n = 78). 36% (n = 39) of neonates had ICH, being mainly small in size. Chi-square test showed a relationship between neurodevelopmental outcome and initial MRI. Unadjusted logistic regression showed that neonates presenting MRI and MRS signs of HIE have 6.23 times higher odds for delayed mental development (OR = 6.2292; CI95% = [1.2642; 30.6934], p = 0.0246), than infants without imaging alterations; with no ICH effect on outcome. Adjustment for clinical and imaging parameters did not change the pattern of results, i.e. HIE remained an independent risk factor for delayed neurodevelopment (OR = 6.2496; CI95% = [1.2018; 32.4983], p = 0.0294), while ICH remained to have no significant effect. CONCLUSION: HIE related MRI abnormalities proved to be important prognostic factors of poor outcome in cooled asphyxiated infants when present, suggesting that early MRI with MRS is beneficial for prognostication. Interestingly, ICHs present in about one third of all cases had no significant effect on neurodevelopmental outcome, despite the known hemostasis altering effects of hypothermia.

Prognostic value of early, conventional proton magnetic resonance spectroscopy in cooled asphyxiated infants.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) commonly leads to neurodevelopmental impairment, raising the need for prognostic tools which may guide future therapies in time. Prognostic value of proton MR spectroscopy (H-MRS) between 1 and 46 days of age has been extensively studied; however, the reproducibility and generalizability of these methods are controversial in a general clinical setting. Therefore, we investigated the prognostic performance of conventional H-MRS during first 96 postnatal hours in hypothermia-treated asphyxiated neonates. METHODS: Fifty-one consecutive hypothermia-treated HIE neonates were examined by H-MRS at three echo-times (TE = 35, 144, 288 ms) between 6 and 96 h of age, depending on clinical stability. Patients were divided into favorable (n = 35) and unfavorable (n = 16) outcome groups based on psychomotor and mental developmental index (PDI and MDI, Bayley Scales of Infant Development II) scores (≥ 70 versus < 70 or death, respectively), assessed at 18-26 months of age. Associations between 36 routinely measured metabolite ratios and outcome were studied. Age-dependency of metabolite ratios in whole patient population was assessed. Prognostic performance of metabolite ratios was evaluated by Receiver Operating Characteristics (ROC) analysis. RESULTS: Three metabolite ratios showed significant difference between outcome groups after correction for multiple testing (p < 0.0014): myo-inositol (mIns)/N-acetyl-aspartate (NAA) height, mIns/creatine (Cr) height, both at TE = 35 ms, and NAA/Cr height at TE = 144 ms. Assessment of age-dependency showed that all 3 metabolite ratios (mIns/NAA, NAA/Cr and mIns/Cr) stayed constant during first 96 postnatal hours, rendering them optimal for prediction. ROC analysis revealed that mIns/NAA gives better prediction for outcome than NAA/Cr and mIns/Cr with cut-off values 0.6798 0.6274 and 0.7798, respectively, (AUC 0.9084, 0.8396 and 0.8462, respectively, p < 0.00001); mIns/NAA had the highest specificity (95.24%) and sensitivity (84.62%) for predicting outcome of neonates with HIE any time during the first 96 postnatal hours. CONCLUSIONS: Our findings suggest that during first 96 h of age even conventional H-MRS could be a useful prognostic tool in predicting the outcome of asphyxiated neonates; mIns/NAA was found to be the best and age-independent predictor.