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ImportanceQuantification of bilirubin in blood is essential for early diagnosis and timely treatment of neonatal hyperbilirubinemia. Handheld point-of-care (POC) devices may overcome the current issues with conventional laboratory-based bilirubin (LBB) quantification.ObjectiveTo systematically evaluate the reported diagnostic accuracy of POC devices compared with LBB quantification.Data SourcesA systematic literature search was conducted in 6 electronic databases (Ovid MEDLINE, Embase, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, CINAHL, and Google Scholar) up to December 5, 2022.Study SelectionStudies were included in this systematic review and meta-analysis if they had a prospective cohort, retrospective cohort, or cross-sectional design and reported on the comparison between POC device(s) and LBB quantification in neonates aged 0 to 28 days. Point-of-care devices needed the following characteristics: portable, handheld, and able to provide a result within 30 minutes. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline.Data Extraction and SynthesisData extraction was performed by 2 independent reviewers into a prespecified, customized form. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analysis was performed of multiple Bland-Altman studies using the Tipton and Shuster method for the main outcome.Main Outcomes and MeasuresThe main outcome was mean difference and limits of agreement in bilirubin levels between POC device and LBB quantification. Secondary outcomes were (1) turnaround time (TAT), (2) blood volumes, and (3) percentage of failed quantifications.ResultsTen studies met the inclusion criteria (9 cross-sectional studies and 1 prospective cohort study), representing 3122 neonates. Three studies were considered to have a high risk of bias. The Bilistick was evaluated as the index test in 8 studies and the BiliSpec in 2. A total of 3122 paired measurements showed a pooled mean difference in total bilirubin levels of −14 μmol/L, with pooled 95% CBs of −106 to 78 μmol/L. For the Bilistick, the pooled mean difference was −17 μmol/L (95% CBs, −114 to 80 μmol/L). Point-of-care devices were faster in returning results compared with LBB quantification, whereas blood volume needed was less. The Bilistick was more likely to have a failed quantification compared with LBB.Conclusions and RelevanceDespite the advantages that handheld POC devices offer, these findings suggest that the imprecision for measurement of neonatal bilirubin needs improvement to tailor neonatal jaundice management.

Introduction: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. Methods: In a single centre prospective cohort study, we included infants with a gestational age Results: We included 45 infants, with a median gestational age of 27 weeks. The mean daily NISS score was 66.5 (SD 8.7), with highest scores in the first 7 days of life. Scores decreased the slowest for the lowest gestational ages, in particular for nursing scores, rather than skin-breaking, monitoring and imaging, and medical morbidity-related scores. Adjusted for gestational age, infants with lower Apgar scores, sepsis, intraventricular haemorrhages, and on mechanical ventilation had significantly higher cumulative NISS scores at 7, 14, and 28 days. Conclusion: NISS scores varied greatly within infants and over time, with the highest mean scores in the first week after birth. The course of declining NISS scores in the first 28 days depended on gestational age at birth.

Item does not contain fulltext Ceftazidime is an antibiotic commonly used to treat bacterial infections in term neonates undergoing controlled therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy after perinatal asphyxia. We aimed to describe the population pharmacokinetics (PK) of ceftazidime in asphyxiated neonates during hypothermia, rewarming, and normothermia and propose a population-based rational dosing regimen with optimal PK/pharmacodynamic (PD) target attainment. Data were collected in the PharmaCool prospective observational multicenter study. A population PK model was constructed, and the probability of target attainment (PTA) was assessed during all phases of controlled TH using targets of 100% of the time that the concentration in the blood exceeds the MIC (T(>MIC)) (for efficacy purposes and 100% T(>4×MIC) and 100% T(>5×MIC) to prevent resistance). A total of 35 patients with 338 ceftazidime concentrations were included. An allometrically scaled one-compartment model with postnatal age and body temperature as covariates on clearance was constructed. For a typical patient receiving the current dose of 100 mg/kg of body weight/day in 2 doses and assuming a worst-case MIC of 8 mg/L for Pseudomonas aeruginosa, the PTA was 99.7% for 100% T(>MIC) during hypothermia (33.7°C; postnatal age [PNA] of 2 days). The PTA decreased to 87.7% for 100% T(>MIC) during normothermia (36.7°C; PNA of 5 days). Therefore, a dosing regimen of 100 mg/kg/day in 2 doses during hypothermia and rewarming and 150 mg/kg/day in 3 doses during the following normothermic phase is advised. Higher-dosing regimens (150 mg/kg/day in 3 doses during hypothermia and 200 mg/kg/day in 4 doses during normothermia) could be considered when achievements of 100% T(>4×MIC) and 100% T(>5×MIC) are desired.

ObjectivesTo describe characteristics of neonates with severe neonatal hyperbilirubinaemia (SNH) and to gain more insight in improvable factors that may have contributed to the development of SNH.Design and settingDescriptive study, based on national Dutch perinatal audit data on SNH from 2017 to 2019.PatientsNeonates, born ≥35 weeks of gestation and without antenatally known severe blood group incompatibility, who developed hyperbilirubinaemia above the exchange transfusion threshold.Main outcome measuresCharacteristics of neonates having SNH and corresponding improvable factors.ResultsDuring the 3-year period, 109 neonates met the eligibility criteria. ABO antagonism was the most frequent cause (43%). All neonates received intensive phototherapy and 30 neonates (28%) received an exchange transfusion. Improvable factors were mainly related to lack of knowledge, poor adherence to the national hyperbilirubinaemia guideline, and to incomplete documentation and insufficient communication of the a priori hyperbilirubinaemia risk assessment among healthcare providers. A priori risk assessment, a key recommendation in the national hyperbilirubinaemia guideline, was documented in only six neonates (6%).ConclusionsSNH remains a serious threat to neonatal health in the Netherlands. ABO antagonism frequently underlies SNH. Lack of compliance to the national guideline including insufficient a priori hyperbilirubinaemia risk assessment, and communication among healthcare providers are important improvable factors. Implementation of universal bilirubin screening and better documentation of the risk of hyperbilirubinaemia may enhance early recognition of potentially dangerous neonatal jaundice.

BACKGROUND AND OBJECTIVES Physicians and parents of critically ill neonates and children receiving intensive care have to make decisions on the child’s behalf. Throughout the child’s illness and treatment trajectory, adequately discussing uncertainties with parents is pivotal because this enhances the quality of the decision-making process and may positively affect the child’s and parents’ well-being. We investigated how physicians discuss uncertainty with parents and how this discussion evolves over time during the trajectory. METHODS We asked physicians working in the NICU and PICU of 3 university medical centers to audio record their conversations with parents of critically ill children from the moment doubts arose whether treatment was in the child’s best interests. We qualitatively coded and analyzed the anonymized transcripts, thereby using the software tool MAXQDA 2020. RESULTS Physicians were found to adapt the way they discussed uncertainty with parents to the specific phase of the child’s illness and treatment trajectory. When treatment options were still available, physicians primarily focused on uncertainty related to diagnostic procedures, treatment options, and associated risks and effects. Particularly when the child’s death was imminent, physicians had less “scientific” guidance to offer. They eliminated most uncertainty and primarily addressed practical uncertainties regarding the child’s dying process to offer parents guidance. CONCLUSIONS Our insights may increase physicians’ awareness and enhance their skills in discussing uncertainties with parents tailored to the phase of the child’s illness and treatment trajectory and to parental needs in each specific phase.

ObjectiveIn the Netherlands, the threshold for offering active treatment for spontaneous birth was lowered from 25+0 to 24+0 weeks’ gestation in 2010. This study aimed to evaluate the impact of guideline implementation on survival and causes and timing of death in the years following implementation.DesignNational cohort study, using data from the Netherlands Perinatal Registry.PatientsThe study population included all 3312 stillborn and live born infants with a gestational age (GA) between 240/7 and 266/7 weeks born between January 2011 and December 2017. Infants with the same GA born between January 2007 and December 2009 (N=1400) were used as the reference group.Main outcome measuresSurvival to discharge, as well as cause and timing of death.ResultsAfter guideline implementation, there was a significant increase in neonatal intensive care unit (NICU) admission rate for live born infants born at 24 weeks’ GA (27%–69%, pConclusionsImplementation of the 2010 guideline resulted as expected in increased NICU admissions rate and postnatal survival of infants born at 24 weeks’ GA. In the years after implementation, a shift in cause of death was seen from respiratory insufficiency towards necrotising enterocolitis and sepsis.

Contains fulltext : 235444.pdf (Publisher’s version ) (Open Access) PURPOSE: Compare patients treated for Retinopathy of Prematurity (ROP) in two consecutive periods. METHODS: Retrospective inventory of anonymized neonatal and ophthalmological data of all patients treated for ROP from 2010 to 2017 in the Netherlands, subdivided in period (P)1: 1-1-2010 to 31-3-2013 and P2: 1-4-2013 to 31-12-2016. Treatment characteristics, adherence to early treatment for ROP (ETROP) criteria, outcome of treatment and changes in neonatal parameters and policy of care were compared. RESULTS: Overall 196 infants were included, 57 infants (113 eyes) in P1 and 139 (275 eyes) in P2, indicating a 2.1-fold increase in ROP treatment. No differences were found in mean gestational age (GA) (25.9 ± 1.7 versus 26.0 ± 1.7 weeks, p = 0.711), mean birth weight (791 ± 311 versus 764 ± 204 grams, p = 0.967) and other neonatal risk factors for ROP. In P2, the number of premature infants born

Introduction: There is little evidence to guide the timing of delivery of women with early-onset severe preeclampsia. We hypothesize that immediate delivery is not inferior for neonatal outcome but reduces maternal complications compared with temporizing management. Material and methods: This Dutch multicenter open-label randomized clinical trial investigated non-inferiority for neonatal outcome of temporizing management as compared with immediate delivery (TOTEM NTR 2986) in women between 27+5 and 33+5 weeks of gestation admitted for early-onset severe preeclampsia with or without HELLP syndrome. In participants allocated to receive immediate delivery, either induction of labor or cesarean section was initiated at least 48 hours after admission. Primary outcomes were adverse perinatal outcome, defined as a composite of severe respiratory distress syndrome, bronchopulmonary dysplasia, culture proven sepsis, intraventricular hemorrhage grade 3 or worse, periventricular leukomalacia grade 2 or worse, necrotizing enterocolitis stage 2 or worse, and perinatal death. Major maternal complications were secondary outcomes. It was estimated 1130 women needed to be enrolled. Analysis was by intention-to-treat. Results: The trial was halted after 35 months because of slow recruitment. Between February 2011 and December 2013, a total of 56 women were randomized to immediate delivery (n = 26) or temporizing management (n = 30). Median gestational age at randomization was 30 weeks. Median prolongation of pregnancy was 2 days (interquartile range 1-3 days) in the temporizing management group. Mean birthweight was 1435 g after immediate delivery vs 1294 g after temporizing management (P =.14). The adverse perinatal outcome rate was 55% in the immediate delivery group vs 52% in the temporizing management group (relative risk 1.06; 95% confidence interval 0.67-1.70). In both groups there was one neonatal death and no maternal deaths. In the temporizing treatment group, one woman experienced pulmonary edema and one placental abruption. Analyses of only the singleton pregnancies did not result in other outcomes. Conclusions: Early termination of the trial precluded any conclusions for the main outcomes. We observed that temporizing management resulted in a modest prolongation of pregnancy without changes in perinatal and maternal outcome. Conducting a randomized study for this important research question did not prove feasible.

BACKGROUND Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment. METHODS In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of

IntroductionSevere neonatal hyperbilirubinaemia can place a neonate at risk for acute bilirubin encephalopathy and kernicterus spectrum disorder. Early diagnosis is essential to prevent these deleterious sequelae. Currently, screening by visual inspection followed by laboratory-based bilirubin (LBB) quantification is used to identify hyperbilirubinaemia in neonates cared for at home in the Netherlands. However, the reliability of visual inspection is limited. We aim to evaluate the effectiveness of universal transcutaneous bilirubin (TcB) screening as compared with visual inspection to: (1) increase the detection of hyperbilirubinaemia necessitating treatment, and (2) reduce the need for heel pricks to quantify bilirubin levels. In parallel, we will evaluate a smartphone app (Picterus), and a point-of-care device for quantifying total bilirubin (Bilistick) as compared with LBB.Methods and analysisWe will undertake a multicentre prospective cohort study in nine midwifery practices across the Netherlands. Neonates born at a gestational age of 35 weeks or more are eligible if they: (1) are at home at any time between days 2 and 8 of life; (2) have their first midwife visit prior to postnatal day 6 and (3) did not previously receive phototherapy. TcB and the Picterus app will be used after visual inspection. When LBB is deemed necessary based on visual inspection and/or TcB reading, Bilistick will be used in parallel. The coprimary endpoints of the study are: (1) hyperbilirubinaemia necessitating treatment; (2) the number of heel pricks performed to quantify LBB. We aim to include 2310 neonates in a 2-year period. Using a decision tree model, a cost-effectiveness analysis will be performed.Ethics and disseminationThis study has been approved by the Medical Research Ethical Committee of the Erasmus MC Rotterdam, Netherlands (MEC-2020-0618). Parents will provide written informed consent. The results of this study will be published in peer-reviewed journals.Trial registration numberDutch Trial Register (NL9545).

Introduction: Retinopathy of prematurity (ROP) remains an important cause for preventable blindness. Aside from gestational age (GA) and birth weight, risk factor assessment can be important for determination of infants at risk of (severe) ROP. Methods: Prospective, multivariable risk-analysis study (NEDROP-2) was conducted, including all infants born in 2017 in the Netherlands considered eligible for ROP screening by pediatricians. Ophthalmologists provided data of screened infants, which were combined with risk factors from the national perinatal database (Perined). Clinical data and potential risk factors were compared to the first national ROP inventory (NEDROP-1, 2009). During the second period, more strict risk factor-based screening inclusion criteria were applied. Results: Of 1,287 eligible infants, 933 (72.5%) were screened for ROP and matched with the Perined data. Any ROP was found in 264 infants (28.3% of screened population, 2009: 21.9%) and severe ROP (sROP) (stage ≥3) in 41 infants (4.4%, 2009: 2.1%). The risk for any ROP is decreased with a higher GA (odds ratio [OR] 0.59 and 95% confidence interval [CI] 0.54–0.66) and increased for small for GA (SGA) (1.73, 1.11–2.62), mechanical ventilation >7 days (2.13, 1.35–3.37) and postnatal corticosteroids (2.57, 1.44–4.66). For sROP, significant factors were GA (OR 0.37 and CI 0.27–0.50), SGA (OR 5.65 and CI 2.17–14.92), postnatal corticosteroids (OR 3.81 and CI 1.72–8.40), and perforated necrotizing enterocolitis (OR 7.55 and CI 2.29–24.48). Conclusion: In the Netherlands, sROP was diagnosed more frequently since 2009. No new risk factors for ROP were determined in the present study, apart from those already included in the current screening guideline.

Background and Aims Retinopathy of prematurity (ROP) is a severe disease in preterm infants. It is seen more frequently in Low‐Middle Income Countries (LMIC) like Indonesia compared to High‐Income Countries (HIC). Risk factors for ROP development are ‐extreme‐ preterm birth, use of oxygen, neonatal infections, respiratory problems, inadequate nutrition, and blood and exchange transfusions. In this paper, we give an overview of steps that can be taken in LMIC to prevent ROP and provide guidelines for screening and treating ROP. Methods Based on the literature search and data obtained by us in Indonesia's studies, we propose guidelines for the prevention, screening, and treatment of ROP in preterm infants in LMIC. Results Prevention of ROP starts before birth with preventing preterm labor, transferring a mother who might deliver

Background Severe hyperbilirubinemia is more frequent in low- and middle-income countries such as Indonesia than in high-income countries. One of the contributing factors might be the lack of adherence to existing guidelines on the diagnosis and treatment of hyperbilirubinemia. We developed a new national guideline for hyperbilirubinemia management in Indonesia. To help healthcare workers use this guideline, a web-based decision support tool application may improve both the adherence to the guideline and the care for infants with hyperbilirubinemia. Methods We developed a web-based application (BiliNorm) to be used on a smartphone that displays the bilirubin level of the patient on the nomogram and advises about the treatment that should be started. Healthcare workers of two teaching hospitals in East Java, Indonesia, were trained on the use of BiliNorm. At 6 months after the introduction, a questionnaire was sent to those who worked with the application enquiring about their experiences. An observational study was conducted in two time epochs. A chart review of infants with hyperbilirubinemia in the two hospitals was sent. The appropriateness of hyperbilirubinemia management during a 6-month period before BiliNorm introduction was compared to that during a 7-month period after its introduction. Results A total of 43 participants filled in the questionnaire, the majority (72%) of them indicated that BiliNorm was well received and easy to use. Moreover, 84% indicated that BiliNorm was helpful for the decision to start phototherapy. Chart review of 255 infants before BiliNorm introduction and that of 181 infants after its introduction indicated that significantly more infants had received treatment according to the guideline (38% vs 51%, p = 0.006). Few infants received phototherapy, but bilirubin level was not measured (14% vs 7%, p = 0.024). There was no difference in the proportion of infants who were over- and under-treated (34% vs 32% and 14% vs 10%, respectively). Conclusions The web-based decision tool BiliNorm appears to be a valuable application. It is easy to use for healthcare workers and helps them adhere to the guideline. It improves the care for infants with hyperbilirubinemia and may help reduce the incidence of severe hyperbilirubinemia in Indonesia.

Background: Our double-blind, placebo-controlled, randomised trial investigating systemic hydrocortisone in mechanically ventilated preterm infants (gestational age

Background Scaling up neonatal care facilities in developing countries can improve survival of newborns. Recently, the only tertiary neonatal care facility in Suriname transitioned to a modern environment in which interventions to improve intensive care were performed. This study evaluates impact of this transition on referral pattern and outcomes of newborns. Methods A retrospective chart study amongst newborns admitted to the facility was performed and outcomes of newborns between two 9-month periods before and after the transition in March 2015 were compared. Results After the transition more intensive care was delivered (RR 1.23; 95% CI 1.07–1.42) and more outborn newborns were treated (RR 2.02; 95% CI 1.39–2.95) with similar birth weight in both periods (P=0.16). Mortality of inborn and outborn newborns was reduced (RR 0.62; 95% CI 0.41–0.94), along with mortality of sepsis (RR 0.37; 95% CI 0.17–0.81) and asphyxia (RR 0.21; 95% CI 0.51–0.87). Mortality of newborns with a birth weight

BACKGROUND: Hyperbilirubinemia guidelines are based on total serum bilirubin (TSB), in combination with either gestational age (GA) or birth weight (BW), postnatal age and specific risk factors. However, TSB is a poor predictor of bilirubin-induced neurotoxicity (BIND). Free unconjugated bilirubin (UCBfree) and the UCBfree/TSB ratio are more directly related to BIND, but data on their postnatal courses are unknown.AIMS: To characterize the postnatal courses of UCBfree and UCBfree/TSB ratio, and assess their relationships with clinical characteristics.SUBJECTS: 72 preterm infants≤32weeks GA, admitted to the University Medical Center Groningen, The Netherlands.STUDY DESIGN: During the first postnatal week, bilirubin plasma parameters were analyzed and their relationship with clinical parameters was analyzed. Postnatal changes were analyzed using Generalized Estimating Equations. Data are expressed as medians [ranges].RESULTS: Less than 10% of the cohort (GA: 29 [26-31] weeks; BW: 1165 [600-1975] g) showed hyperbilirubinemic risk factors. We observed a large variation in UCBfree (27 [1-197] nmol/L), that could partly be explained by postnatal age and gender, but not by other risk factors. Maximal UCBfree levels of 50 [13-197] nmol/L occurred at day 4 and were higher in males. In contrast to TSB, UCBfree/TSB ratios (0.19 [0.01-1.04]) were higher in infants with low GA/BW.CONCLUSION: UCBfree levels vary considerably in preterm infants, despite a low incidence of hyperbilirubinemic risk factors and similar TSB-based phototherapy treatment. UCBfree could not be predicted by GA or BW, but UCBfree/TSB ratios are highest in the smallest preterms, while they have the lowest TSB levels.

Hyperbilirubinemia in the newborn occurs more frequently in Indonesia. Therefore, it is important that pediatric residents in Indonesia acquire adequate knowledge of hyperbilirubinemia management. This study aims to determine the pediatric residents' knowledge on hyperbilirubinemia management, whether they follow recommended guidelines, and whether differences exist between five large Indonesian teaching hospitals. We handed out a 25-question questionnaire on hyperbilirubinemia management to pediatric residents at five teaching hospitals. A total of 250 questionnaires were filled in completely, ranging from 14 to 113 respondents per hospital. Approximately 76% of the respondents used the Kramer score to recognize neonatal jaundice. Twenty-four percent correctly plotted the total serum bilirubin levels (TSB) on the phototherapy (PT) nomograms provided by the American Academy of Pediatrics (AAP) and the National Institute for Health and Care Excellence (NICE) for full-term and nearly full-term infants. Regarding preterm infants, Hyperbilirubinemia, newborn infants, knowledge, residents, guidelines.

Hyperbilirubinemia in the newborn occurs more frequently in Indonesia. Therefore, it is important that pediatric residents in Indonesia acquire adequate knowledge of hyperbilirubinemia management. This study aims to determine the pediatric residents' knowledge on hyperbilirubinemia management, whether they follow recommended guidelines, and whether differences exist between five large Indonesian teaching hospitals. We handed out a 25-question questionnaire on hyperbilirubinemia management to pediatric residents at five teaching hospitals. A total of 250 questionnaires were filled in completely, ranging from 14 to 113 respondents per hospital. Approximately 76% of the respondents used the Kramer score to recognize neonatal jaundice. Twenty-four percent correctly plotted the total serum bilirubin levels (TSB) on the phototherapy (PT) nomograms provided by the American Academy of Pediatrics (AAP) and the National Institute for Health and Care Excellence (NICE) for full-term and nearly full-term infants. Regarding preterm infants35 weeks' gestational age, 66% of the respondents plotted TSB levels on the AAP nomogram, although this nomogram doesn't apply to this category of infants. Seventy percent of residents knew when to perform an exchange transfusion whereas 27% used a fixed bilirubin cut-off value of 20 mg/dL. Besides PT, 25% reported using additional pharmaceutical treatments, included albumin, phenobarbitone, ursodeoxycholic acid and immunoglobulins, while 47% of the respondents used sunlight therapy, as alternative treatment. The limited knowledge of the pediatric residents could be one factor for the higher incidence of severe hyperbilirubinemia and its sequelae. The limited knowledge of the residents raises doubts about the knowledge of the supervisors and the training of the residents since pediatric residents receive training from their supervisors.

BACKGROUND: The Thompson encephalopathy score is a clinical score to assess newborns suffering from perinatal asphyxia. Previous studies revealed a high sensitivity and specificity of the Thompson encephalopathy score for adverse outcomes (death or severe disability). Because the Thompson encephalopathy score was developed before the use of therapeutic hypothermia, its value was reassessed. OBJECTIVE: The purpose of this study was to assess the association of the Thompson encephalopathy score with adverse short-term outcomes, defined as death before discharge, development of severe epilepsy, or the presence of multiple organ failure in asphyxiated newborns undergoing therapeutic hypothermia. METHODS: The study period ranged from November 2010 to October 2014. A total of 12 tertiary neonatal intensive care units participated. Demographic and clinical data were collected from the "PharmaCool" multicenter study, an observational cohort study analyzing pharmacokinetics of medication during therapeutic hypothermia. With multiple logistic regression analyses the association of the Thompson encephalopathy scores with outcomes was studied. RESULTS: Data of 142 newborns were analyzed (male: 86; female: 56). Median Thompson score was 9 (interquartile range: 8 to 12). Median gestational age was 40 weeks (inter quartile range 38 to 41), mean birth weight was 3362 grams (standard deviation: 605). All newborns manifested perinatal asphyxia and underwent therapeutic hypothermia. Death before discharge occurred in 23.9% and severe epilepsy in 21.1% of the cases. In total, 59.2% of the patients had multiple organ failure. The Thompson encephalopathy score was not associated with multiple organ failure, but a Thompson encephalopathy score >= 12 was associated with death before discharge (odds ratio: 3.9; confidence interval: 1.3 to 11.2) and with development of severe epilepsy (odds ratio: 8.4; confidence interval: 2.5 to 27.8). CONCLUSION: The Thompson encephalopathy score is a useful clinical tool, even in cooled asphyxiated newborns. A score >= 12 is associated with adverse outcomes (death before discharge and development of severe epilepsy). The Thompson encephalopathy score is not associated with the development of multiple organ failure.

Aim(s) Little is known about the pharmacokinetic (PK) properties of gentamicin in newborns undergoing controlled hypothermia after suffering from hypoxic-ischaemic encephalopathy due to perinatal asphyxia. This study prospectively evaluates and describes the population PK of gentamicin in these patients. Methods Demographic, clinical and laboratory data of patients included in a multicentre prospective observational cohort study (the 'PharmaCool Study') were collected. A non-linear mixed-effects regression analysis (nonmem®) was performed to describe the population PK of gentamicin. The most optimal dosing regimen was evaluated based on simulations of the final model. Results A total of 47 patients receiving gentamicin were included in the analysis. The PK were best described by an allometric two compartment model with gestational age (GA) as a covariate on clearance (CL). During hypothermia the CL of a typical patient (3 kg, GA 40 weeks, 2 days post-natal age (PNA)) was 0.06 l kg-1 h-1 (inter-individual variability (IIV) 26.6%) and volume of distribution of the central compartment (Vc) was 0.46 l kg-1 (IIV 40.8%). CL was constant during hypothermia and rewarming, but increased by 29% after reaching normothermia (>96 h PNA). Conclusions This study describes the PK of gentamicin in neonates undergoing controlled hypothermia. The 29% higher CL in the normothermic phase compared with the preceding phases suggests a delay in normalization of CL after rewarming has occurred. Based on simulations we recommend an empiric dose of 5 mg kg-1 every 36 h or every 24 h for patients with GA 36-40 weeks and GA 42 weeks, respectively.

Background: Much controversy exists about the optimal management of a patent ductus arteriosus (PDA) in preterm infants, especially in those born at a gestational age (GA) less than 28weeks. No causal relationship has been proven between a (haemodynamically significant) PDA and neonatal complications related to pulmonary hyperperfusion and/or systemic hypoperfusion. Although studies show conflicting results, a common understanding is that medical or surgical treatment of a PDA does not seem to reduce the risk of major neonatal morbidities and mortality. As the PDA might have closed spontaneously, treated children are potentially exposed to iatrogenic adverse effects. A conservative approach is gaining interest worldwide, although convincing evidence to support its use is lacking. Methods: This multicentre, randomised, non-inferiority trial is conducted in neonatal intensive care units. The study population consists of preterm infants (GA1.5mm. Early treatment (between 24 and 72h postnatal age) with the cyclooxygenase inhibitor(COXi) ibuprofen (IBU) is compared with an expectative management (no intervention intended to close a PDA). The primary outcome is the composite of mortality, and/or necrotising enterocolitis (NEC) Bell stage ≥ IIa, and/or bronchopulmonary dysplasia (BPD) defined as the need for supplemental oxygen, all at a postmenstrual age (PMA) of 36weeks. Secondary outcome parameters are short term sequelae of cardiovascular failure, comorbidity and adverse events assessed during hospitalization and long-term neurodevelopmental outcome assessed at a corrected age of 2 years. Consequences regarding health economics are evaluated by cost effectiveness analysis and budget impact analysis. Discussion: As a conservative approach is gaining interest, we investigate whether in preterm infants, born at a GA less than 28weeks, with a PDA an expectative management is non-inferior to early treatment with IBU regarding to the composite outcome of mortality and/or NEC and/or BPD at a PMA of 36weeks., SCOPUS: ar.j, info:eu-repo/semantics/published

Severe hyperbilirubinemia, which may result in kernicterus, is seen more frequently in low and middle-income countries, such as Indonesia, than in high-income countries. In Indonesia midwives, general practitioners (GPs), and pediatricians are involved in the care of jaundiced newborn infants. It is unknown whether the high incidence of severe hyperbilirubinemia in this country is related to a lack of awareness of existing hyperbilirubinemia guidelines issued by, for example, the World Health Organization, the American Academy of Pediatrics, or the Indonesian Health Ministry, or to a lack of adherence to such guidelines. The aim of this questionnaire study was to assess health professionals' awareness of existing guidelines and their adherence to these guidelines in daily practice. We handed out a ten-question questionnaire to midwives, GPs, and pediatricians that included questions about the professionals themselves as well as clinical questions. The midwives completed 291 questionnaires, the GPs 206, and the pediatricians 154, all of which we used for our analysis. Almost 30% of the midwives and 23% of the GPs were either unaware of any existing guidelines or they did not adhere to them. Only 54% of the midwives recognized the warning signs of severe hyperbilirubinemia correctly, compared to 68% of the GPs and 89% of the pediatricians. Twenty-eight percent of the midwives and 31% of the GPs indicated that their first follow-up visit was after 72 hours, while 90% of them discharged infants after less than 48 hours after birth. The awareness of and adherence to guidelines for preventing and treating hyperbilirubinemia is low amongst the midwives and GPs in Indonesia. This may be an important contributing factor in the high incidence of severe hyperbilirubinemia in Indonesia.

The therapeutic effect of moderate hypothermia in infants with HIE after perinatal asphyxia can be counteracted by stress which should therefore be minimized. Objective: of study was to gain insight in the COMFORTNeo-scale to measure stress during therapeutic hypothermia. Stress was measured prospectively by means of the COMFORTNeo-scale (CNS), twice a day, during hypothermia-, rewarming- and stabilization phase in a cohort of 133 neonates with perinatal asphyxia who participated in the PharmaCool study. A total of 994 CNS scores were collected; median score CNS 9 (IQR 7–11). Despite analgesic, sedative and anticonvulsant drugs 10% of the scores indicated moderate to severe stress during treatment. The use of these drugs as well as mechanical ventilation interfered with CNS score (respectively odds ratio 0.74 and 0.61) Interference of aEEG, hypothermia phase and gender were not confirmed. The COMFORTNeo-scale can, with the necessary caution, be used for the assessment of stress during therapeutic hypothermia treatment. Other options should be explored.

AIM: The aim of the study was to determine whether regional cerebral tissue oxygen saturation (rc SO2 ) and fractional tissue oxygen extraction (FTOE), using near-infrared spectroscopy, are associated with neurodevelopmental outcome of preterm infants.METHOD: We measured rc SO2 on days 1, 2, 3, 4, 5, 8, and 15 after birth in 83 preterm infants (RESULTS: We followed up 67 infants. The lower quartile (P25-50 ) and highest quartile (P75-100 ) of rc SO2 on day 1 were associated with poorer cognitive outcome (p=0.044 and p=0.008 respectively). A lower area under the curve (AUC; over 15d) of rc SO2 was associated with poorer cognitive outcome (p=0.014). The lower quartile (P25-50 ) AUC of rc SO2 was associated with poorer fine motor outcome (p=0.004). The amount of time rc SO2 INTERPRETATION: Cerebral oxygen saturation during the first 2 weeks after birth is associated with neurodevelopmental outcome of preterm infants at 2 to 3 years. High and low rc SO2 on day 1 were associated with poorer neurodevelopmental outcome.

Treatment for unconjugated hyperbilirubinemia is predominantly based on one parameter, i.e., total serum bilirubin (TSB) levels. Yet, overt kernicterus has been reported in preterm infants at relatively low TSB levels, and it has been repeatedly shown that free unconjugated bilirubin (freeUCB) levels, or bilirubin/albumin (B/A) ratios for that matter, are more closely associated with bilirubin neurotoxicity. In this article, we review bilirubin-albumin binding, UCBfree levels, and B/A ratios in addition to TSB levels to individualize and optimize treatment especially in preterm infants. Methods to measure bilirubin-albumin binding or UCBfree are neither routinely performed in Western clinical laboratories nor incorporated in current management guidelines on unconjugated hyperbilirubinemia. For bilirubin-albumin binding, this seems justified because several of these methods have been challenged, and sufficiently powered prospective trials on the clinical benefits are lacking. Technological advances in the measurement of UCBfree may provide a convenient means for integrating UCBfree measurements into routine clinical management of jaundiced infants. A point-of-care method, as well as determination of UCBfree levels in various newborn populations, is desirable to learn more about variations in time and how various clinical pathophysiological conditions affect UCBfree levels. This will improve the estimation of approximate UCBfree levels associated with neurotoxicity. To delineate the role of UCBfree in the management of jaundiced (preterm) infants, trials are needed using UCBfree as treatment parameter. The additional use of the B/A ratio in jaundiced preterms has been evaluated in the Bilirubin Albumin Ratio Trial (BARTrial; Clinical Trials: ISRCTN74465643) but failed to demonstrate better neurodevelopmental outcome in preterm infants

Neuroprotective controlled therapeutic hypothermia is the standard of care for newborns suffering perinatal asphyxia. Antibiotic drugs, such as amikacin, gentamicin, and vancomycin are frequently administered during controlled hypothermia, which possibly alters their pharmacokinetic (PK) and pharmacodynamic (PD) profiles. In order to examine this effect an LC-MS/MS method for the simultaneous quantification of amikacin, the major gentamicin components (gentamicin C, Cl a and C2), and vancomycin in plasma was developed. In 25 mu L plasma proteins were precipitated with trichloroacetic acid (TCA) and detection of the components was achieved using ion-pair reversed phase chromatography coupled with electrospray ionization tandem mass spectrometry. The chromatographic runtime was 7.5 min per sample. Calibration standards were prepared over a range of 0.3-50 mg L-1 for amikacin and gentamicin and 1.0-100 mg L-1 for vancomycin. At LLOQ accuracy was between 103 and 120% and imprecision was less than 19%. For concentrations above LLOQ accuracy ranged from 98% to 102% and imprecision was less than 6%. Process efficiency, ionization efficiency, and recovery were acceptable. Samples and stock solutions were stable during the time periods and at the different temperatures examined. The applicability of the method was shown by analysing plasma samples from 3 neonatal patients. The developed method allows accurate and precise simultaneous quantification of amikacin, gentamicin, and vancomycin in a small volume (25 mu L) of plasma. (C) 2014 Elsevier B.V. All rights reserved.

Our objective was to analyze the relationship between transcutaneous bilirubin (TcB) measured on an unexposed area of skin and total serum bilirubin (TSB) in preterm infants before, during, and after phototherapy (PT). For this purpose paired TSB and TcB levels were measured daily during the first ten days after birth in preterm infants of less than 32 weeks' gestation. TcB was measured with a Dräger Jaundice Meter JM-103 on the covered hipbone. Agreement between TSB and TcB levels was assessed before, during, and after PT. True negative and corresponding false negative percentages were calculated using different TcB cut-off levels. Data are presented as mean (±SD). We obtained 856 paired TcB and TSB levels in 109 preterm infants (66 boys, gestational age 29.4 ± 1.6 weeks and birth weight 1282 g ± 316 g). We found that the difference between TSB and TcB before PT was significantly lower, 44 (±36) μmol/L, than the difference during and after PT, 61 (±29) μmol/L and 63 (±25) μmol/L, respectively; P < 0.01. Blood sampling could be reduced by 42%, with 2% false negatives, when 50 μmol/L was added to the TcB level at 70% of the PT threshold. Our conclusion is that phototherapy enhances underestimation of TSB by TcB in preterms, even if measured on unexposed skin. The use of specific TcB cut-off levels substantially reduces the need for TSB measurements.

Background: The occurrence of severe neonatal hyperbilirubinemia (SH) is partly attributed to nonhospitalized perinatal care. The Netherlands have a high frequency of home births and nonhospitalized perinatal care, and the incidence of SH is unknown. Objective: To assess the effects of home births and early hospital discharge on the incidence of SH in term-born infants in the Netherlands. Methods: In this nationwide prospective surveillance study between 2005 and 2009, infants (≥37 weeks GA) were included if total serum bilirubin (TSB) was ≥500 µmol/l or if they received an exchange transfusion when TSB was ≥340 µmol/l. Results: Seventy-one infants had SH (incidence 10.4/100,000); 43 had a TSB ≥500 μmol/l (incidence 6.3/100,000) and 45 (63%) underwent an exchange transfusion. 26% of the infants with SH were born at home, which is similar to 22% of all term infants who are born at home in the Netherlands (p = 0.41). Maximum TSB levels were similar in infants born at home (523 ± 114 μmol/l) and infants born in hospital (510 ± 123 μmol/l; p = 0.70). Of the 51 infants born in hospital, 33 were discharged and readmitted with SH, with maximal TSB levels (567 ± 114 μmol/l), which were higher than in infants who remained hospitalized (406 ± 47 μmol/l; p = 0.0001). Conclusion: The incidence of severe hyperbilirubinemia in term-born infants in the Netherlands is 10.4 per 100,000, which is similar to other developed countries. Home birth and early hospital discharge do not necessarily lead to a higher incidence of SH, provided that perinatal home care is well organized.

Contains fulltext : 168757.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To determine outcome of children born with isolated gastroschisis (no extra-gastrointestinal congenital abnormalities). STUDY DESIGN: International cohort study and meta-analysis. PRIMARY OUTCOME: time to full enteral feeding (TFEF); secondary outcomes: Duration of mechanical ventilation, length of stay (LOS), mortality and differences in outcome between simple and complex gastroschisis (complex; born with bowel atresia, volvulus, perforation or necrosis). To compare the cohort study results with literature three databases were searched. Studies were eligible for inclusion if cases were born in developed countries with isolated gastroschisis after 1990, number of cases >20 and TFEF was reported. RESULTS: The cohort study included 204 liveborn cases of isolated gastroschisis. The TFEF, median duration of ventilation and LOS was, 26days (range 6-515), 2days (range 0-90) and 33days (range 11-515), respectively. Overall mortality was 10.8%. TFEF and LOS were significantly longer (P

Introduction: We conducted a review of the evidence which contributes to the current care of jaundiced newborn infants. Methods: Literature was searched for reviews and randomized controlled trials (RCTs). Results: Six Cochrane reviews and eight other reviews and eighteen recent RCTs are discussed. Conclusions: Many children still suffer life-long consequences of severe hyperbilirubinaemia, which could almost always have been prevented relatively easily. Up to date, guidelines summarizing the available evidence into unambiguous recommendations are needed to guide healthcare professionals in the prevention, diagnosis and treatment for infants with hyperbilirubinaemia.

Unconjugated hyperbilirubinaemia occurs in almost all premature infants and is potentially neurotoxic. Treatment is based on total serum bilirubin (TSB), but treatment thresholds are not evidence based. Free bilirubin (Bf) - that is, not bound to albumin, seems a better parameter for bilirubin neurotoxicity, but measurements of Bf are not available in clinical practice. The bilirubin/albumin (B/A) ratio is considered a surrogate parameter for Bf and an interesting additional parameter in the management of hyperbilirubinaemia. This paper reviewed the evidence supporting the use of B/A ratios for predicting bilirubin-induced neurological dysfunction (BIND) including neurodevelopmental delay in jaundiced premature infants (gestational age less than 32 weeks). A literature search was performed and six publications reviewed regarding B/A ratios in the management and outcome of jaundiced premature infants. No prospective clinical trials had been undertaken to show whether bilirubin-induced neurotoxicity is reduced or whether unnecessary treatment is avoided by using the B/A ratio in addition to TSB. Recently, a randomised controlled trial evaluating the effect of the additional use of the B/A ratio on neurodevelopmental outcome in jaundiced premature infants has been initiated. Based on the prevailing evidence many authorities suggest that the additional use of the B/A ratio may be valuable when evaluating jaundiced premature infants.

ObjectiveTo test the ability of the Ages and Stages Questionnaire, Third Edition (ASQ3) to help identify or exclude neurodevelopmental impairment (NDI) in very preterm-born children at the corrected age of two.MethodsWe studied the test results of 224 children, born at ResultsWe found 61 (27%) children with abnormal ASQ3 scores, and 10 (4.5%) children who had NDI with original BSIDIII thresholds (ConclusionThe Ages and Stages Questionnaire is a simple, valid and cost-effective screening tool to help identify and exclude NDI in very preterm-born children at the corrected age of two years

The purpose of this study was to evaluate whether avoiding interruption of ventilation during surfactant instillation improves the effects on lung function and surfactant distribution and whether it prevents the adverse effects on blood pressure and cerebral blood flow. The study was performed using rabbits with severe respiratory failure induced by lung lavages. These rabbits were randomized to 99mTc-Nanocoll labeled surfactant instillation through a side lumen of the endotracheal tube without interrupting ventilation or instillation during a short interruption of ventilation. After surfactant instillation with interruption of ventilation, PaO2 rose from 8.7+/-1.3 to 24.9+/-6.4 kPa (mean+/-SEM). Without interruption, PaO2 rose from 8.4+/-0.8 to 32.4+/-4.3 kPa. PaCO2 decreased with interruption from 4.69+/-0.51 to 3.61+/-0.26 kPa and without interruption from 5.06+/-0.41 to 4.13+/-0.23 kPa. Dynamic and static compliance indices were not statistically different after both procedures. Surfactant distribution tended to be less nonuniform after instillation without interrupting ventilation. In contrast, avoidance of interruption of ventilation resulted in less uniform lobar distribution and less peripheral deposition of surfactant. By instillation with interruption, blood pressure increased quickly (28+/-6.6%), followed by a 22+/-5.3% decrease. Blood pressure increased quickly (16+/-4.2%), followed by a 40+/-10% decrease by surfactant instillation without interruption. Cerebral blood flow, measured by an ultrasonic transit time flow probe on the carotid artery, increased quickly (45+/-14%), followed by a 64+/-11% decrease with interruption, whereas it increased 15+/-4.9% (p = 0.06 versus with interruption) and decreased 61+/-13% without interruption of ventilation. Therefore, avoiding interruption of ventilation during surfactant instillation tends to prevent the potential adverse effects of a rapid rise in cerebral blood flow, and furthermore, tends to improve uniformity of surfactant distribution, whereas having no detrimental effect on respiratory function.

Surfactant nebulization improves lung function at low alveolar doses of surfactant. However, efficiency of nebulization is low, and lung deposition seems to depend on lung aeration. High frequency ventilation (HFV) has been shown to improve lung aeration. We hypothesize that the combination of HFV and surfactant nebulization may benefit lung deposition of surfactant and consequently, lung function. The aim of this study was to compare the effect of surfactant nebulization versus instillation during HFV on lung function, surfactant distribution, and cerebral blood flow. Therefore, severe respiratory failure was induced by lung lavages in 18 rabbits. HFV was applied: frequency = 8 Hz, mean airway pressure = 12 cm H2O, amplitude = 100%, fraction of inspired O-2 = 1.0. Technetium-99m-labeled surfactant (Alveofact, 100 mg/kg of BW) was nebulized or instilled (n = 6 each). Six other rabbits did not receive surfactant (control, HFV only). We found that after instillation partial arterial O-2 tension increased from 7.0 kPa (95% confidence interval, 6.3-8.0 kPa) to 34 kPa (16-51 kPa), and during nebulization from 7.0 kPa (6.0-9.0 kPa) to 46 kPa (27-58 kPa). Partial arterial CO, tension decreased after instillation from 6.1 kPa (5.3-7.1 kPa) to 4.8 kPa (3.9-5.6 kPa), and during nebulization, after an initial rise, it decreased from 6.3 kPa (5.3-7.4 kPa) to 4.9 kPa (4.4-5.6 kPa). Both treatments resulted in nonuniform distribution. Surfactant deposition after nebulization was 9.8%, Instillation resulted in a drop of mean arterial blood pressure of 17% (8-31%), and an even more pronounced drop in cerebral blood flow of 39% (18-57%). Nebulization did not affect blood pressure. Cerebral blood flow decreased with a maximum of 27% (10-37%). We conclude that surfactant nebulization during HFV improves lung function in rabbits with severe respiratory failure, without improving distribution, but with less effects on blood pressure and cerebral blood flow, when compared with surfactant instillation.

Objective: Surfactant nebulisation is a promising alternative to surfactant instillation in newborns with the respiratory distress syndrome. Although less surfactant is deposited in the lung, it improves gas exchange, probably due to a superior distribution. We hypothesize that a more uniform distribution of nebulised surfactant results in a more uniform pulmonary blood flow and consequently a more efficient gas exchange. We asked whether the pulmonary blood flow changes after surfactant replacement, and to what extent pulmonary blood flow is influenced by the amount of surfactant deposition. Furthermore, we investigated whether sufficient nebulised surfactant is deposited in the lungs to achieve a sustained improvement in lung function, Interventions: Surfactant was nebulised or instilled, or saline was nebulised, in 18 lung-lavaged rabbits. After 2 h the rabbits were weaned from mechanical ventilation to continuous positive airway pressure: 40 % oxygen. We measured blood gasses, dynamic lung compliance, surfactant distribution using 99m technetium nanocoll label, and the pulmonary blood flow distribution, using microspheres. Results: Partial pressure of oxygen in arterial blood and lung compliance were significantly higher after surfacfant nebulisation than after saline nebulisation. Surfactant instillation gave a superior effect with respect to these variables, Nebulised surfactant was distributed more uniformly over the lungs than instilled surfactant. Although pulmonary blood flow changed over time, it remained uniformly distributed following both modes of surfactant treatment, Surfactant deposition was neither strongly related to pulmonary blood now nor strongly related to the change in blood flow. Conclusions: Although nebulised surfactant is uniformly distributed, we can provide no evidence that: this results in a more uniform pulmonary blood flow distribution, Therefore, other than a superior surfactant distribution, no additional reason tvas found for the efficient gas exchange after nebulisation.

Objective: The objectives of this study were, to select a nebuliser first, that operates safely in a neonatal ventilator setting and, second, that is most efficient. Thirdly, we studied the particle sizes of the surfactant aerosol. Fourthly, we studied where the nebulised surfactant is deposited in the tubing system of the ventilator. Finally, we studied whether nebulisation influences the composition and biophysical properties of surfactant.Measurements and results: Safety was assessed by measuring ''mean airway pressures'' in a test lung before, during and after surfactant nebulisation, for three jet nebulisers. The MiniNEB did not alter these pressures, and is thus safe, whereas the other two nebulisers (Intersurgical and Flo-Thru) increased these pressures. The efficiency of nebulisation was assessed by measuring the amount of phospholipid deposited in the test lung. The MiniNEB showed the highest efficiency: 10 % versus 1-3 % of the other two nebulisers. The particle sizes of surfactant aerosol were assessed by the laser diffraction method. Seventy percent of the particles were 1-5 mu m. The deposition of surfactant aerosol in the tubing system was assessed by nebulising surfactant that was labelled with Tc-99m Nanocoll. Afterwards the tubing system was imaged using a gamma camera. The majority of surfactant was deposited in the expiratory hose (28 %), nebuliser (20 %), Y-piece (16 %) and expiratory filter (12 %). Finally the phospholipid composition, spreading velocity, static and dynamic surface tensions were assessed for the nebulised surfactant and compared to the stock surfactant. In addition, nebulised surfactant was instilled in premature rabbits and tidal volumes were measured to assess the dose-response relation. We found that neither the composition nor biophysical properties had been altered by nebulisation.Conclusions: The MiniNEB nebulised surfactant safely in a neonatal ventilator setting with respect to airway pressures. The efficiency of nebulisation is low: the majority of the surfactant aerosol is deposited in the expiratory tubing. The surfactant composition and function is not altered by nebulisation. Therefore the nebulisation of surfactant is feasible, but efforts should be made to improve the efficiency of this procedure.

BACKGROUND: Severe unconjugated hyperbilirubinemia may cause deafness. In the Netherlands, 25% lower total serum bilirubin (TSB) treatment thresholds were recently implemented for preterm infants. OBJECTIVE: To determine the rate of hearing loss in jaundiced preterms treated at high or at low TSB thresholds. DESIGN/METHODS: In this retrospective study conducted at two neonatal intensive care units in the Netherlands, we included preterms (gestational age 35 dB). RESULTS: There were 479 patients in the high and 144 in the low threshold group. Both groups had similar gestational ages (29.5 weeks) and birth weights (1300 g). Mean and mean peak TSB levels were significantly lower after the implementation of the novel thresholds: 152 ± 43 µmol/L and 212 ± 52 µmol/L versus 131 ± 37 µmol/L and 188 ± 46 µmol/L for the high versus low thresholds, respectively (P

In the 19th century it was already known that unconjugated hyperbilirubinemia could potentially harm the central nervous system of jaundiced newborn infants. Yellow staining of deep brain nuclei in jaundiced infants was first reported in 1847. The term kernicterus (in German, kern = nucleus; in Greek, ikterus = yellow) was first denoted in 1903 to describe the pathological findings of this specific yellow staining pattern [1]. Nowadays, kernicterus is not only used to describe the pathological findings, but also to describe the clinical findings of acute and/or chronic bilirubin encephalopathy in jaundiced infants [2, 3]. Although acute kernicterus is an unambiguous clinical disorder in severely jaundiced newborn infants with the possibility of permanent sequelae, subtle forms of bilirubin encephalopathy referred to as bilirubin-induced neurological dysfunction, also known as BIND have evolved more recently [4]. This chapter aims to describe the pathophysiology of bilirubin neurotoxicity, its clinical spectrum and diagnostic tools. Novel treatment modalities to prevent infants from developing severe unconjugated hyperbilirubinemia and bilirubin neurotoxicity will be highlighted.

Background Randomized controlled trials have shown that treatment of chronically ventilated preterm infants after the first week of life with dexamethasone reduces the incidence of the combined outcome death or bronchopulmonary dysplasia (BPD). However, there are concerns that dexamethasone may increase the risk of adverse neurodevelopmental outcome. Hydrocortisone has been suggested as an alternative therapy. So far no randomized controlled trial has investigated its efficacy when administered after the first week of life to ventilated preterm infants. Methods/Design The SToP-BPD trial is a randomized double blind placebo controlled multicenter study including 400 very low birth weight infants (gestational age < 30 weeks and/or birth weight < 1250 grams), who are ventilator dependent at a postnatal age of 7 - 14 days. Hydrocortisone (cumulative dose 72.5 mg/kg) or placebo is administered during a 22 day tapering schedule. Primary outcome measure is the combined outcome mortality or BPD at 36 weeks postmenstrual age. Secondary outcomes are short term effects on the pulmonary condition, adverse effects during hospitalization, and long-term neurodevelopmental sequelae assessed at 2 years corrected gestational age. Analysis will be on an intention to treat basis. Discussion This trial will determine the efficacy and safety of postnatal hydrocortisone administration at a moderately early postnatal onset compared to placebo for the reduction of the combined outcome mortality and BPD at 36 weeks postmenstrual age in ventilator dependent preterm infants. Trial registration number Netherlands Trial Register (NTR): NTR2768

Bilirubin encephalopathy and kernicterus are preventable conditions. Nevertheless cases continue to occur. It is difficult to identify those infants who may develop severe hyperbilirubinemia, because icterus neonatorum occurs in most newborns. The aim of this guideline is to reduce the incidence of severe neonatal hyperbilirubinemia and bilirubin encephalopathy, and at the same time to minimise the risk of unintended side effects. At the initiative of the Dutch Pediatric Association and with methodological support from the Dutch Institute for Healthcare Improvement (CBO), a multidisciplinary working group adapted the clinical practice guideline on hyperbilirubinemia of the American Academy of Pediatrics (AAP) to the Dutch situation. This guideline provides recommendations for the prevention, diagnosis and treatment of hyperbilirubinemia in neonates (or= 35 weeks). For all newborns a risk assessment for the development of hyperbilirubinemia is made and they are to be systematically assessed during the first week of life. The guideline provides various intervention thresholds for risk groups, recommendations for the use of intravenous immunoglobulin in the event of severe hyperbilirubinemia on the basis of blood group antagonisms, and recommendations for conjugated hyperbilirubinemia. During the transfer of care, information about the risk factors in particular must be satisfactorily passed on.