The use of transcutaneous bilirubin nomograms for the prevention of bilirubin neurotoxicity in the neonates.

Purpose: Although neonatal jaundice is a ubiquitous and predominantly benign phenomenon, the risk of neurotoxicity exists in a number of infants with unconjugated hyperbilirubinemia. Plotting bilirubin values on nomograms enables clinicians to employ an anticipatory and individualized approach with the goal of avoiding excessive hyperbilirubinemia and preventing acute bilirubin encephalopathy and its progression to kernicterus. We aimed to construct nomograms for White term infants based on transcutaneous bilirubin (TcB) measurements using a JM-105 device. Methods: TcB measurements were taken in infants at ages ranging from 0 to 96 postnatal hours. We then constructed hour-specific TcB nomograms from forehead and sternum measurements in infants who did not require subsequent phototherapy. Results: We included 2,981 TcB measurements taken on the forehead and 2,977 measurements taken on the sternum in 301 White term newborn infants. We assessed the predictive abilities of the nomograms at six postnatal time intervals using receiver operating characteristic curves. The areas under the curves indicated reasonable prediction of hyperbilirubinemia requiring phototherapy, except for the forehead measurement taken within the first 12 h of life. Sensitivity tended to rise as postnatal age increased. Conclusion: The nomograms illustrate dermal bilirubin dynamics in White term neonates during the first 4 days of life. They may be useful tools to predict individualized risk of hyperbilirubinemia requiring treatment, and to plan optimal follow-up of infants at risk of bilirubin neurotoxicity.

Survey of transfusion practices in preterm infants in Europe.

BACKGROUND: Preterm infants commonly receive red blood cell (RBC), platelet and fresh frozen plasma (FFP) transfusions. The aim of this Neonatal Transfusion Network survey was to describe current transfusion practices in Europe and to compare our findings to three recent randomised controlled trials to understand how clinical practice relates to the trial data. METHODS: From October to December 2020, we performed an online survey among 597 neonatal intensive care units (NICUs) caring for infants with a gestational age (GA) of <32 weeks in 18 European countries. RESULTS: Responses from 343 NICUs (response rate: 57%) are presented and showed substantial variation in clinical practice. For RBC transfusions, 70% of NICUs transfused at thresholds above the restrictive thresholds tested in the recent trials and 22% below the restrictive thresholds. For platelet transfusions, 57% of NICUs transfused at platelet count thresholds above 25×109/L in non-bleeding infants of GA of <28 weeks, while the 25×109/L threshold was associated with a lower risk of harm in a recent trial. FFP transfusions were administered for coagulopathy without active bleeding in 39% and for hypotension in 25% of NICUs. Transfusion volume, duration and rate varied by factors up to several folds between NICUs. CONCLUSIONS: Transfusion thresholds and aspects of administration vary widely across European NICUs. In general, transfusion thresholds used tend to be more liberal compared with data from recent trials supporting the use of more restrictive thresholds. Further research is needed to identify the barriers and enablers to incorporation of recent trial findings into neonatal transfusion practice.

The Common Haplotype GATGACA in Surfactant-Protein B Gene Is Protective for Respiratory Distress Syndrome in Preterm Neonates.

Background: Respiratory distress syndrome (RDS), a disorder of primary surfactant deficiency resulting in pulmonary insufficiency, remains a significant problem for preterm neonates. Associations between genetic variants of surfactant proteins and RDS have been reported, but haplotypes of the surfactant protein B gene (SFTPB) have not been studied. The aim of the study was to prove the hypothesis that certain haplotypes of SFTPB may be protective or risk factors for RDS. Methods: The study was performed with 149 preterm infants, born <34 weeks of gestation, with 86 infants with mild RDS or without RDS (control group) and 63 infants with severe RDS (patient group). RDS was considered severe if multiple doses of exogenous surfactant and/or mechanical ventilation within the first 72 h of life were needed. The venous blood sample was used for the analysis of gene polymorphisms associated with RDS, genotyping, and haplotype estimation. Multivariate logistic regression analysis and the odds ratio were calculated to detect the contribution of the studied variables to the development of RDS. Results: A new association of the common single nucleotide polymorphism (SNP) rs2304566 with RDS in premature infants was detected. Analysis of rs2304566 polymorphisms using a logistic regression model showed that there are two significant predictors inversely related to the occurrence of RDS (Apgar score of 5 min, CT and TT genotype in rs2304566 polymorphism). Gestational age, birth weight, and sex have border significance. Moreover, in the patient group, the frequency of the GATGACA haplotype in the SFTPB gene was lower (p = 0.037), and the GATGGCA haplotype was higher (p = 0.059) in comparison with the control group. Conclusion: The common haplotype GATGACA of the SFTPB gene can be protective against RDS in preterm infants. The trend of a higher frequency of GATGGCA in the SFTPB gene in infants with severe RDS suggests that this haplotype may be a risk factor for RDS susceptibility.

N-Acetylcysteine in Mechanically Ventilated Rats with Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome: The Effect of Intravenous Dose on Oxidative Damage and Inflammation.

Treatment of acute respiratory distress syndrome (ARDS) is challenging due to its multifactorial aetiology. The benefit of antioxidant therapy was not consistently demonstrated by previous studies. We evaluated the effect of two different doses of intravenous (i.v.) N-acetylcysteine (NAC) on oxidative stress, inflammation and lung functions in the animal model of severe LPS-induced lung injury requiring mechanical ventilation. Adult Wistar rats with LPS (500 µg/kg; 2.2 mL/kg) were treated with i.v. NAC 10 mg/kg (NAC10) or 20 mg/kg (NAC20). Controls received saline. Lung functions, lung oedema, total white blood cell (WBC) count and neutrophils count in blood and bronchoalveolar lavage fluid, and tissue damage in homogenized lung were evaluated. NAC significantly improved ventilatory parameters and oxygenation, reduced lung oedema, WBC migration and alleviated oxidative stress and inflammation. NAC20 in comparison to NAC10 was more effective in reduction of oxidative damage of lipids and proteins, and inflammation almost to the baseline. In conclusion, LPS-instilled and mechanically ventilated rats may be a suitable model of ARDS to test the treatment effects at organ, systemic, cellular and molecular levels. The results together with literary data support the potential of NAC in ARDS.

Accuracy of enhanced transcutaneous bilirubinometry according to various measurement sites.

OBJECTIVE: The goal of the study was to provide missing data on the accuracy of enhanced transcutaneous bilirubinometry in a monoracial population of term neonates, considering three different measurement sites. MATERIAL AND METHODS: Transcutaneous bilirubin was measured using the JM-105 device on the forehead, chest, and abdomen. Blood sampling for total serum bilirubin concentration has been performed within 10 minutes of transcutaneous measurements. Paired transcutaneous bilirubin and total serum bilirubin measurements were statistically analyzed. RESULTS: The study group consisted of 102 healthy term Slovak infants. The correlation between total serum bilirubin and transcutaneous bilirubin was significant (coefficient of determination R2: 0.9045 forehead, 0.8808 sternum, 0.8467 abdomen). Transcutaneous measurements underestimated serum bilirubin levels significantly when total serum bilirubin values were higher than 15 mg/dL, irrespective of the site of transcutaneous measurements. The lowest mean difference between total serum bilirubin and transcutaneous bilirubin was identified on the sternum (median: -1.1 mg/dL). The area under the curve was >0.97 and >0.93 for detecting total serum bilirubin levels >10 mg/dL and >13 mg/dL, respectively, for all measurement sites. Transcutaneous measurements on the forehead and sternum provided very high sensitivity, with the best performance at the forehead. CONCLUSION: Transcutaneous bilirubinometry using an enhanced device is an accurate, sensitive, and convenient screening method in term Caucasian neonates. Transcutaneous bilirubin measurements on the forehead, sternum, and abdomen are reliable, with the best performance on the forehead. It is necessary to confirm higher transcutaneous bilirubin values with a total serum bilirubin measurement.

The Effect of Modified Porcine Surfactant Alone or in Combination with Polymyxin B on Lung Homeostasis in LPS-Challenged and Mechanically Ventilated Adult Rats.

The study aimed to prove the hypothesis that exogenous surfactant and an antibiotic polymyxin B (PxB) can more effectively reduce lipopolysaccharide (LPS)-induced acute lung injury (ALI) than surfactant treatment alone, and to evaluate the effect of this treatment on the gene expression of surfactant proteins (SPs). Anesthetized rats were intratracheally instilled with different doses of LPS to induce ALI. Animals with LPS 500 µg/kg have been treated with exogenous surfactant (poractant alfa, Curosurf®, 50 mg PL/kg b.w.) or surfactant with PxB 1% w.w. (PSUR + PxB) and mechanically ventilated for 5 hrs. LPS at 500 µg/kg increased lung edema, oxidative stress, and the levels of proinflammatory mediators in lung tissue and bronchoalveolar lavage fluid (BALF). PSUR reduced lung edema and oxidative stress in the lungs and IL-6 in BALF. This effect was further potentiated by PxB added to PSUR. Exogenous surfactant enhanced the gene expression of SP-A, SP-B, and SP-C, however, gene expression for all SPs was reduced after treatment with PSUR + PxB. In mechanically ventilated rats with LPS-induced ALI, the positive effect of exogenous surfactant on inflammation and oxidative stress was potentiated with PxB. Due to the tendency for reduced SPs gene expression after surfactant/PxB treatment topical use of PxB should be considered with caution.

Recombinant Human Superoxide Dismutase and N-Acetylcysteine Addition to Exogenous Surfactant in the Treatment of Meconium Aspiration Syndrome.

This study aimed to evaluate the molecular background of N-acetylcysteine (NAC) and recombinant human superoxide dismutase (rhSOD) antioxidant action when combined with exogenous surfactant in the treatment of meconium aspiration syndrome (MAS), considering redox signalling a principal part of cell response to meconium. Young New Zealand rabbits were instilled with meconium suspension (Mec) and treated by surfactant alone (Surf) or surfactant in combination with i.v. NAC (Surf + NAC) or i.t. rhSOD (Surf + SOD), and oxygen-ventilated for 5 h. Dynamic lung-thorax compliance, mean airway pressure, PaO2/FiO2 and ventilation efficiency index were evaluated every hour; post mortem, inflammatory and oxidative markers (advanced oxidation protein products, total antioxidant capacity, hydroxynonenal (HNE), p38 mitogen activated protein kinase, caspase 3, thromboxane, endothelin-1 and secretory phospholipase A2) were assessed in pulmonary tissue homogenates. rhSOD addition to surfactant improved significantly, but transiently, gas exchange and reduced levels of inflammatory and oxidative molecules with higher impact; Surf + NAC had stronger effect only on HNE formation, and duration of treatment efficacy in respiratory parameters. In both antioxidants, it seems that targeting reactive oxygen species may be strong supporting factor in surfactant treatment of MAS due to redox sensitivity of many intracellular pathways triggered by meconium.

Clinical considerations when treating neonatal aspiration syndromes.

INTRODUCTION: In physiological conditions, neonatal airways are well-protected against aspiration of fluid or particulate material into the lungs, with laryngeal chemoreflex (LCR) being the most powerful mechanism. Failure of this protection allows substances to enter the lower airways, which starts a series of pathophysiological events initiated by inflammation and surfactant inactivation. The condition is defined as neonatal acute respiratory distress syndrome (ARDS), and its symptoms can range from mild respiratory distress to respiratory failure, often accompanied by persistent pulmonary hypertension (PPHN), in turn even leading to death. The management, therefore, may be very challenging. Areas covered: This review covers protection mechanisms of the neonatal lower airways, the etiology, and pathophysiology of neonatal aspiration syndrome (NAS), its definition in view of current literature, possible treatment options, and future trends. Expert commentary: Inflammation and secondary surfactant deficiency stand in the foreground of neonatal aspiration. Management focuses mainly on appropriate oxygenation, ventilation, improvement in PPHN, and maintenance of systemic circulation, which is largely symptomatic and supportive. Future research is required to evaluate the justification of using exogenous surfactants, antibiotics, anti-inflammatory and antioxidative drugs, or their combinations.

Heart rate variability in healthy term newborns is related to delivery mode: a prospective observational study.

BACKGROUND: Early postnatal period is characterized by dramatic adaptation changes of cardiovascular and respiratory systems in newborns. There is still insufficient data regarding maturation of autonomic regulatory mechanisms in neonates early after delivery. Aim of this study was to analyze cardiac autonomic regulation in newborns within the first few postnatal days in relation to different modes of delivery using time and spectral heart rate variability analysis. METHODS: Eutrophic healthy term newborns (n = 46) were divided into three groups according to the delivery mode: vaginal delivery (VD group; n = 16), vaginal delivery with epidural analgesia (EDA group; n = 16), and caesarean section under general anesthesia (CS group; n = 14). Heart rate variability (HRV), blood pressure (BP), and blood oxygen saturation (SpO2) were measured within the first two hours after birth and on the third to fourth postnatal day. HRV parameters were evaluated in the time domain (RR intervals, mean square of successive differences - MSSD) and frequency domain (total spectral power - TP, absolute and relative low and high frequency powers). RESULTS: The HRV spectral analysis showed significantly higher relative power of the high-frequency band (HF%) in the VD group compared to the CS group early after delivery (p = 0.002). HRV parameters and BP significantly increased on the third to fourth postnatal day in all groups (p < 0.05). No significant differences in basic characteristics, BP and SpO2 were identified between groups during both measurements. CONCLUSIONS: HRV analysis revealed higher cardiovagal modulation in spontaneously born newborns without analgesia compared to neonates born by caesarean section. It could represent a potential pathomechanism that leads to discrete abnormal neurocardiac regulation associated with higher risk for worsened postnatal adaptation of cardiovascular system in surgically delivered neonates.

Phosphodiesterase inhibitors: Potential role in the respiratory distress of neonates.

Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyze the hydrolysis of phosphodiester bonds of 3',5' cyclic adenosine and guanosine monophosphate (cAMP and cGMP). PDEs control hydrolysis of cyclic nucleotides in many cells and tissues. Inhibition of PDEs by selective or nonselective PDE inhibitors represents an effective targeted strategy for the treatment of various diseases including respiratory disorders. Recent data have demonstrated that PDE inhibitors can also be of benefit in respiratory distress in neonates. This article outlines the pharmacological properties of nonselective and selective PDE inhibitors and provides up-to-date information regarding their use in experimental models of neonatal respiratory distress as well as in clinical studies.

Genetic association of single nucleotide polymorphisms of FZD4 and BDNF genes with retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a multifactorial disease occurring in preterm neonates, caused by incorrect development of retinal blood vessels. It has been suggested that, in addition to gestational age, weight, and oxygen supplementation, genetic factors can play a role in the pathogenesis of ROP. METHODS: In the present prospective study, 97 neonates were enrolled based on the gestational age and weight, and genomic DNA from patients diagnosed with ROP and premature newborns without ROP was collected. The DNA sequence of protein coding and 5´and 3´ untranslated regions (UTRs) of the frizzled-4 (FZD4) gene and the genotype of the locus rs7934165:G˃A (NM_170731.4: c.3 + 10976 C˃T) within the brain-derived neurotrophic factor gene (BDNF) were determined. RESULTS: We detected a significant association between rs61749246:C˃A (NM_012193.3: c.*2G˃T) and ROP in a general genetic model as well as in a multiplicative model and by the Cochran-Armitage test for trend. Moreover, rs61749246 was strongly associated with ROP, requiring surgical intervention. CONCLUSION: We suggest that rs61749246:C˃A of the FZD4 gene is likely associated with the development of ROP. It is necessary to confirm this suggestion in larger studies.

The early postnatal blood flow characteristics in the superior mesenteric and coeliac arteries in late preterm neonates.

OBJECTIVES: The objective of this study is to evaluate intestinal blood flow changes within the first 72 h in the late preterm infants in comparison with the healthy term neonates. METHODS: In this prospective study, we analyzed Doppler flow velocity waveforms of superior mesenteric artery (SMA) and coeliac trunc (TC) in 20 late preterm and 20 term infants at the age of 2, 24, and 72 h. RESULTS: Significant end-diastolic velocity (end-diastolic velocity (EDV)SMA) rise up to 24 h was documented in all patients (late preterm: -9.32 ± 9.48 to 17.01 ± 6.94; p < .05; term: -8 ± 5.74 to 12.39 ± 3.33; p < .001), associated with a conversion from negative values to positive ones. Reversed blood flow was documented in SMA at 2 h in 75% late preterm neonates. Preterm infants showed significantly higher mean peak systolic velocities (peak systolic velocity (PSV)SMA), end-diastolic velocities (EDVSMA) at 24 h and PSVTC at 72 h than term infants (p < .05). The resistance and pulsatility indices (PI) decreased within 24 h in both groups and inversely reflected the postnatal changes in EDVSMA. Mean PIAMS at 2 h was significantly higher in term neonates. CONCLUSION: Late preterm neonates show similar progressive postnatal increase in blood flow velocities accompanied with a decrease in vascular resistance in SMA and TC then term neonates.

Changes of cardiovascular regulation during rewarming in newborns undergoing whole-body hypothermia.

OBJECTIVES: The aim of the study was to determine changes of oxygenation and cardiovascular parameters during body temperature recovery in newborns undergoing therapeutic hypothermia. DESIGN AND SETTINGS: Three full-term newborns treated by whole-body hypothermia according to TOBY trial were included in the study. They were cooled to body temperature of 33.5 °C for 72 hours, thereafter gradual rewarming was initiated. During rewarming period following parameters were measured: heart rate and heart rate variability, blood pressure, core body temperature, blood oxygen saturation, cerebral and splanchnic tissue oxygenation. In one of the infants Doppler sonography examination of truncus coeliacus and arteria mesenterica superior was performed to assess blood flow in these arteries. RESULTS: During rewarming period the heart rate increased, whereas blood pressure tended to decrease. It was observed ascending trend in parameters of heart rate variability (MSSD and total spectral power) due to increasing spectral activity in LF and also HF bands. Blood oxygen saturation and cerebral tissue oxygenation remained stable, but significant decrease of splanchnic tissue oxygenation was noticed. This finding corresponded to Doppler sonography parameters in arteria mesenterica superior. THE MAIN FINDING: Therapeutic hypothermia and subsequent rewarming in newborns influenced cardiovascular regulation (blood pressure, heart rate, heart rate variability). Body temperature recovery was accompanied by reduction in splanchnic oxygenation and blood flow in superior mesenteric artery. CONCLUSIONS: Body temperature recovery in neonates led to changes in autonomic cardiovascular regulation resulting in redistribution of blood flow to vital organs. Reduction of blood flow to splanchnic organs during heating is a finding that has not been described yet. Further studies are needed to confirm these findings.

Neonatal assessment in the delivery room--Trial to Evaluate a Specified Type of Apgar (TEST-Apgar).

BACKGROUND: Since an objective description is essential to determine infant's postnatal condition and efficacy of interventions, two scores were suggested in the past but weren't tested yet: The Specified-Apgar uses the 5 items of the conventional Apgar score; however describes the condition regardless of gestational age (GA) or resuscitative interventions. The Expanded-Apgar measures interventions needed to achieve this condition. We hypothesized that the combination of both (Combined-Apgar) describes postnatal condition of preterm infants better than either of the scores alone. METHODS: Scores were assessed in preterm infants below 32 completed weeks of gestation. Data were prospectively collected in 20 NICU in 12 countries. Prediction of poor outcome (death, severe/moderate BPD, IVH, CPL and ROP) was used as a surrogate parameter to compare the scores. To compare predictive value the AUC for the ROC was calculated. RESULTS: Of 2150 eligible newborns, data on 1855 infants with a mean GA of 28(6/7) ± 2(3/7) weeks were analyzed. At 1 minute, the Combined-Apgar was significantly better in predicting poor outcome than the Specified- or Expanded-Apgar alone. Of infants with a very low score at 5 or 10 minutes 81% or 100% had a poor outcome, respectively. In these infants the relative risk (RR) for perinatal mortality was 24.93 (13.16-47.20) and 31.34 (15.91-61.71), respectively. CONCLUSION: The Combined-Apgar allows a more appropriate description of infant's condition under conditions of modern neonatal care. It should be used as a tool for better comparison of group of infants and postnatal interventions. TRIAL REGISTRATION: clinicaltrials.gov Protocol Registration System (NCT00623038). Registered 14 February 2008.

Prenatal diagnosis of cardiac rhabdomyoma associated with tuberous sclerosis: report of 3 cases.

Cardiac rhabdomyoma is the most common cardiac tumor in fetal life, accounting for 60-86% of primary fetal cardiac tumors. It is primarily benign, originating form myocardial muscles and consisting of immature myocytes. About 50-60% of these tumors are associated with tuberous sclerosis. In this report, we present the clinical course and discuss the importance of prenatal diagnosis of cardiac tumors and their follow-up after birth.

Very early postnatal changes in splanchnic circulation in term infants.

BACKGROUND: Reversed blood flow has been reported in the superior mesenteric artery (SMA) in 92% of healthy term newborns at 2 h of age. By 24 h after birth the end-diastolic velocity became positive in all of the infants. OBJECTIVE: To characterize hemodynamic changes in the coeliac artery and superior mesenteric artery in healthy term newborns during the first 6 h after birth and to specify the time interval when the negative values of end-diastolic velocity in the superior mesenteric artery become positive. MATERIALS AND METHODS: Our study included 30 healthy term newborns. The blood flow velocity was assessed by Doppler ultrasonography at 2 h, 4 h and 6 h after birth. RESULTS: The end-diastolic velocity in the superior mesenteric artery changed from negative values at the age of 2 h (-0.9 cm/s, range -13.2 to 0.0) to positive (7.08 cm/s, range 6.3 to 13.5, P < 0.001) at 6 h after birth. In the coeliac artery, the end-diastolic velocity increased during this period, but negative values were not observed (11.8 cm/s, range 9.3 to 13.9 at 2 h and 18.03 cm/s, range 14.2 to 27.6 at 6 h). CONCLUSION: Important changes occur in splanchnic circulation during the first 6 h after birth. The rise in end-diastolic velocity in the superior mesenteric artery from negative to positive values in 83% of healthy term newborns is the most important change.

The assessment of intracranial dynamics by transcranial Doppler sonography in perioperative period in paediatric hydrocephalus.

PURPOSE: To evaluate Doppler parameters of anterior cerebral artery (ACA) and relationship to morphological parameters of cerebral ventricles and periventricular brain tissue in paediatric hydrocephalus before and after drainage procedure. METHODS: Forty newborns with hydrocephalus were evaluated before and after the drainage procedure. The morphological parameters of brain (ventricular index, width of ventricles, haemorrhagic lesions, asymmetric ventricular dilatation and dynamics of ventricles) were measured by transcranial ultrasonography. The haemodynamic parameters of ACA (peak systolic blood flow velocity, end-diastolic blood flow velocity and resistance index/RI/) were evaluated by Doppler ultrasonography. The correlation between morphological and haemodynamic parameters was analysed. RESULTS: We found significant decrease of ventricular dilatation, which was accompanied with significant decrease of basal and compressive RI-ACA after drainage procedure. The correlation between basal RI-ACA, compressive RI-ACA and the dynamics of ventricular dilatation was not significant before and after drainage operation, as well. The significant correlation between preoperative basal RI-ACA, postoperative compressive RI-ACA and asymmetry of cerebral ventricles was confirmed. Statistical analysis showed significant correlation between basal RI-ACA, compressive RI-ACA and haemorrhagic lesions after drainage operation. CONCLUSIONS: The results of our study showed the alteration of Doppler parameters of cerebral circulation in newborns with hydrocephalus before the drainage procedure. The successful drainage operation leads to the improvement of haemodynamic parameters of cerebral circulation. However, the statistical analysis showed the influence of some intracranial factors-the asymmetry of dilatation of lateral cerebral ventricles and periventricular haemorrhagic lesions on the Doppler parameters of cerebral circulation.