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[This corrects the article DOI: 10.1371/journal.pone.0297363.].
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AIMS: Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. METHODS: Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. RESULTS: Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5 kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10 mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. CONCLUSION: Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.
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Antibacterianos , Asfixia Neonatal , Hipotermia Induzida , Modelos Biológicos , Vancomicina , Humanos , Recém-Nascido , Vancomicina/farmacocinética , Vancomicina/administração & dosagem , Hipotermia Induzida/métodos , Asfixia Neonatal/terapia , Asfixia Neonatal/tratamento farmacológico , Estudos Prospectivos , Masculino , Feminino , Antibacterianos/farmacocinética , Antibacterianos/administração & dosagem , Área Sob a Curva , Idade Gestacional , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVE: The aim of this study is to assess the neonatal click Auditory Brainstem Response (ABR) results in relation to the subsequently determined mean hearing loss (HL) over 1, 2 and 4 kHz, as well as over 2 and 4 kHz. METHODS: Between 2004-2009, follow-up data were collected from Visual Reinforcement Audiometry (VRA) at 1 and 2 years and playaudiometry at 4 and 8 years of newborns who had failed neonatal hearing screening in the well-baby clinics and who had been referred to a single Speech and Hearing center. Hearing Level data were compared with ABR threshold-levels established during the first months of life. The Two One-Sided Tests equivalence procedure for paired means was applied, using a region of similarity equal to 10 dB. RESULTS: Initially, in 135 out of 172 children referred for diagnostic procedures hearing loss was confirmed in the neonatal period. In 106/135 of the HL children the eight-year follow-up was completed. Permanent conductive HL was established in 5/106 cases; the hearing thresholds were predominantly stable over time. Temporary conductive HL was found in 48/106 cases and the loss disappeared by 4 years of age at the latest. Sensorineural hearing loss (SNHL) was found in 53/106 cases, of which 13 were unilateral and 40 bilateral. ABR levels were equivalent (within a 10 dB range) to VRA levels at age 1 and 2 and play audiometry levels at age 4 and 8, both when VRA and play audiometry were averaged over both frequency ranges. CONCLUSION: Long term follow-up data of children with SNHL suggest that the initial click ABR level established in the first months of life, are equivalent to the hearing threshold measured at the age of 1, 2, 4 and 8 years for both mean frequency ranges. Click ABR can reliably be used as starting point for long-term hearing rehabilitation.
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Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Lactente , Criança , Recém-Nascido , Humanos , Pré-Escolar , Seguimentos , Perda Auditiva/diagnóstico , Perda Auditiva Neurossensorial/diagnóstico , Testes Auditivos , Perda Auditiva Condutiva , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Audição , Limiar Auditivo/fisiologiaRESUMO
OBJECTIVE: Concerns have been raised about the effect of skin color on the accuracy of transcutaneous bilirubin (TcB) measurements, a widely used method for hyperbilirubinemia diagnosis in newborns. Literature is inconclusive, with both reported under- and overestimations of the TcB with increasing skin pigmentation. Therefore, the influence of skin color on TcB measurements was systematically evaluated in a controlled, in vitro setting. METHODS: A bilirubin meter (JM-105) was evaluated on layered phantoms that mimic neonatal skin with varying dermal bilirubin concentrations (0-250 µmol/L) and varying epidermal melanosome volume fractions (0-40%; light-dark skin color). RESULTS: TcB measurements were influenced by skin pigmentation. Larger mimicked melanosome volume fractions and higher bilirubin levels led to larger underestimations of the measured TcB, compared to an unpigmented epidermis. In the in vitro setting of this study, these underestimations amounted to 26-132 µmol/L at a TcB level of 250 µmol/L. CONCLUSION: This in vitro study provides insight into the effect of skin color on TcB measurements: the TcB is underestimated as skin pigmentation increases and this effect becomes more pronounced at higher bilirubin levels. Our results highlight the need for improved TcB meter design and cautious interpretation of TcB readings on newborns with dark skin. IMPACT: Key message: Skin color influences transcutaneous bilirubin measurements: the darker the skin, the larger the underestimation. What this study adds to existing literature: Existing literature is inconclusive regarding the influence of skin color on transcutaneous bilirubin measurements. This study systematically evaluates and clarifies the influence of skin color on transcutaneous bilirubin measurements in a controlled, in vitro setting. IMPACT: This study aids to better interpret the measured TcB level in patients with varying skin colors, and is particularly important when using TcB meters on patients with dark skin colors.
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BACKGROUND: Model validation procedures are crucial when population pharmacokinetic (PK) models are used to develop dosing algorithms and to perform model-informed precision dosing. We have previously published a population PK model describing the PK of gentamicin in term neonates with perinatal asphyxia during controlled therapeutic hypothermia (TH), which showed altered gentamicin clearance during the hypothermic phase dependent on gestational age and weight. In this study, the predictive performance and generalizability of this model were assessed using an independent data set of neonates with perinatal asphyxia undergoing controlled TH. METHODS: The external data set contained a subset of neonates included in the prospective observational multicenter PharmaCool Study. Predictive performance was assessed by visually inspecting observed-versus-predicted concentration plots and calculating bias and precision. In addition, simulation-based diagnostics, model refitting, and bootstrap analyses were performed. RESULTS: The external data set included 323 gentamicin concentrations of 39 neonates. Both the model-building and external data set included neonates from multiple centers. The original gentamicin PK model predicted the observed gentamicin concentrations with adequate accuracy and precision during all phases of controlled TH. Model appropriateness was confirmed with prediction-corrected visual predictive checks and normalized prediction distribution error analyses. Model refitting to the merged data set (n = 86 neonates with 935 samples) showed accurate estimation of PK parameters. CONCLUSIONS: The results of this external validation study justify the generalizability of the gentamicin dosing recommendations made in the original study for neonates with perinatal asphyxia undergoing controlled TH (5 mg/kg every 36 or 24 h with gestational age 36-41 and 42 wk, respectively) and its applicability in model-informed precision dosing.
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Antibacterianos , Asfixia Neonatal , Gentamicinas , Hipotermia Induzida , Modelos Biológicos , Humanos , Gentamicinas/farmacocinética , Gentamicinas/uso terapêutico , Recém-Nascido , Hipotermia Induzida/métodos , Asfixia Neonatal/terapia , Estudos Prospectivos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Masculino , Feminino , Idade GestacionalRESUMO
OBJECTIVE: Birth weight (BW) discordant twins have an increased risk of mortality and morbidity. We aimed to study the effect of BW discordance on the risk of neonatal hearing loss (NHL) in very and extremely preterm twins. STUDY DESIGN: Results of the nationwide newborn hearing screening program in Dutch Neonatal Intensive Care Units and diagnostic examination were centrally registered between 2003 and 2021 and included in this study. We selected twins and singletons with a gestational age (GA) 24- < 32 weeks. Logistic regression analyses were applied to study the effect of BW discordance on the risk of NHL adjusted for BW, GA and sex. Singletons and concordant twins, defined as a BW discordance of ≤20 %, were used as two reference groups. BW discordance was further categorized as medium (>20-30 %) and high (>30 %). RESULTS: In total, 3430 twins (2694 concordant, 428 medium and 308 high BW discordant), and 23,114 singletons were available. Smaller newborns of high BW discordant twins showed an increased risk of NHL compared to singletons (adjusted odds ratio with 95 % confidence interval was 3.56 (2.26-5.60)). Also, smaller newborns of medium and high BW discordant twins showed an increased risk of NHL compared to concordant twins (adjusted odds ratio with 95 % confidence interval were 1.97 (1.13-3.44) and 4.17 (2.56-6.82), respectively). No other statistically significant differences were found. CONCLUSION: BW discordance increased the risk of NHL in the smaller of the twin born very or extremely preterm. This risk increased as the weight difference increased.
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Perda Auditiva , Doenças do Recém-Nascido , Recém-Nascido , Humanos , Lactente , Peso ao Nascer , Lactente Extremamente Prematuro , Mortalidade Infantil , Estudos Retrospectivos , Idade Gestacional , Perda Auditiva/epidemiologiaRESUMO
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.
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Hipotermia Induzida , Hipotermia , Hipóxia-Isquemia Encefálica , Recém-Nascido , Humanos , Ceftazidima/farmacologia , Hipotermia/tratamento farmacológico , Antibacterianos/farmacologiaRESUMO
OBJECTIVE: Observational studies in preterm infants suggest that systemic hydrocortisone improves pulmonary condition but may also lead to systemic adverse effects. We report the short-term pulmonary and systemic effects of hydrocortisone initiated in the second week. DESIGN: Randomised placebo-controlled trial. SETTING: Dutch and Belgian neonatal intensive care units. PATIENTS: Infants born <30 weeks' gestation and/or birth weight <1250 g, and ventilator dependent in the second week of life. INTERVENTION: Infants were randomly assigned to a 22-day course of systemic hydrocortisone (cumulative dose 72.5 mg/kg; n=182) or placebo (n=190). MAIN OUTCOME MEASURES: Data on extubation, ventilator settings, glucose levels, and blood pressure were recorded daily and analysed during the first 7 days of treatment using linear mixed-effects models. RESULTS: Infants in the hydrocortisone group (24.3%) failed extubation less often compared with placebo (38.6%, crude risk difference: -14.3% (95% CI: -23.4% to -4.8%)). The estimated difference in daily rate of change between hydrocortisone and placebo was -0.42 cmH2O (95% CI: -0.48 to -0.36) for mean airway pressure, -0.02 (95% CI: -0.02 to -0.01) for fraction of inspired oxygen, -0.37 (95% CI: -0.44 to -0.30) for respiratory index, 0.14 mmol/L (95% CI: 0.08 to 0.21) for blood glucose levels and 0.83 mm Hg (95% CI: 0.58 to 1.09) for mean blood pressure. CONCLUSIONS: Systemic hydrocortisone initiated between 7 and 14 days after birth in ventilated preterm infants improves pulmonary condition, thereby facilitating weaning and extubation from invasive ventilation. The effects of hydrocortisone on blood glucose levels and blood pressure were mild and of limited clinical relevance. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR2768; https://www.trialregister.nl/trial/2640) and European Union Clinical Trials Register (EudraCT, 2010-023777-19).
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Doenças do Prematuro , Pneumopatias , Lactente , Recém-Nascido , Humanos , Hidrocortisona/efeitos adversos , Recém-Nascido Prematuro , Glicemia , Recém-Nascido de muito Baixo Peso , Doenças do Prematuro/tratamento farmacológicoRESUMO
BACKGROUND: The cephalocaudal progression (CCP) of neonatal jaundice is a well-known phenomenon, but quantitative information on CCP in preterm infants is absent. In this study, CCP was quantified in preterm infants as a function of postnatal age and body location. METHODS: 5.693 transcutaneous bilirubin (TcB) measurements were performed in 101 preterm infants from birth until postnatal day seven at five body locations (forehead, sternum, hipbone, tibia, ankle). Multi-level linear regression analysis was performed to evaluate the CCP as a function of body location and postnatal age. TcB measurements at all body locations and postnatal days were compared to total serum bilirubin (TSB) levels (N = 1.113). RESULTS: The overall average change in ratio of TcB compared to forehead was for sternum +0.04 [95% CI -0.02;0.09]; hipbone +0.05 [0.00;0.01]; tibia -0.33 [-0.38;-0.27] and ankle -0.62 [-0.68;-0.57]. No effect modification of CCP by sex, gestational age, birthweight, phototherapy, and TSB was found. The TcB maximally underestimated the TSB at the ankle -79.5 µmol [-0.1;159.2]. CONCLUSIONS: CCP is present in preterm infants and is relatively stable over time. Since TcB measurements on the tibia and ankle underestimate TSB significantly, we advise to use only measurement locations cephalic from the tibia; i.e., hipbone, sternum, and forehead. IMPACT: Cephalocaudal progression (CCP) of jaundice in preterm infants, assessed by transcutaneous bilirubin (TcB) measurements, is substantial and rather stable over postnatal day 0 to 7. To the best of our knowledge, this study is the first to investigate CCP of jaundice in preterm infants as a function of postnatal age in preterm infants. Our results demonstrate that TcB measurements at the tibia and ankle differ from the TSB beyond the clinically used TcB safety margins. We advise to perform TcB measurements only at locations cephalic from the tibia; i.e., hipbone, forehead, and sternum.
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Icterícia Neonatal , Icterícia , Lactente , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Icterícia Neonatal/diagnóstico , Icterícia Neonatal/terapia , Peso ao Nascer , Bilirrubina , Triagem Neonatal/métodosRESUMO
BACKGROUND: Phototherapy (PT) is the standard treatment of neonatal unconjugated hyperbilirubinemia. The irradiance footprint, i.e., the illuminated area by the PT device with sufficient spectral irradiance, is essential for PT to be effective. Irradiance footprint measurements are not performed in current clinical practice. We describe a user-friendly method to systematically evaluate the high spectral irradiance (HSI) footprint (illuminated area with spectral irradiance of ≥30 µW cm-2 nm-1) of PT devices in clinical practice. MATERIALS AND METHODS: Six commercially available LED-based overhead PT devices were evaluated in overhead configuration with an incubator. Spectral irradiance (µW cm-2 nm-1) and HSI footprint were measured with a radiospectrometer (BiliBlanket Meter II). RESULTS: The average measured spectral irradiance ranged between 27 and 52 µW cm-2 nm-1 and HSI footprint ranged between 67 and 1465 cm2, respectively. Three, two, and one PT devices out of six covered the average BSA of an infant born at 22, 26-32, and 40 weeks of gestation, respectively. CONCLUSION: Spectral irradiance of LED-based overhead PT devices is often lower than manufacturer's specifications, and HSI footprints not always cover the average BSA of a newborn infant. The proposed measurement method will contribute to awareness of the importance of irradiance level as well as footprint measurements in the management of neonatal jaundice. IMPACT: While a sufficient spectral irradiance footprint is essential for PT to be effective, some PT devices have spectral irradiance footprints that are too small to cover the entire body surface area (BSA) of a newborn infant. This study introduces a user-friendly, accessible method to systematically evaluate the spectral irradiance level and footprint of PT devices. This study supports awareness on the role of the spectral irradiance footprint in the efficacy of PT devices. Irradiance footprint can be easily measured during phototherapy with the proposed method.
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Hiperbilirrubinemia Neonatal , Icterícia Neonatal , Humanos , Hiperbilirrubinemia Neonatal/terapia , Recém-Nascido , Icterícia Neonatal/terapia , FototerapiaRESUMO
The mammillary bodies (MB) and hippocampi are important for memory function and are often affected following neonatal hypoxic ischemic encephalopathy (HIE). The aim of this study was to assess neurodevelopmental outcome in 10-year-old children with HIE with and without therapeutic hypothermia. Additional aims were to assess the associations between MB atrophy, brain volumes (including the hippocampi), white matter microstructure and neurodevelopmental outcome at school-age. Ten-year-old children with HIE were included, who were treated with therapeutic hypothermia (n = 22) or would have qualified but were born before this became standard of care (n = 28). Children completed a neuropsychological and motor assessment and MRI. Mammillary bodies were scored as normal or atrophic at 10 years. Brain volumes were segmented on childhood MRI and DTI scans were analysed using tract-based spatial statistics. Children with HIE suffered from neurocognitive and memory problems at school-age, irrespective of hypothermia. Hippocampal volumes and MB atrophy were associated with total and performance IQ, processing speed and episodic memory in both groups. Normal MB and larger hippocampi were positively associated with global fractional anisotropy. In conclusion, injury to the MB and hippocampi was associated with neurocognition and memory at school-age in HIE and might be an early biomarker for neurocognitive and memory problems.
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Atrofia/fisiopatologia , Hipocampo/fisiopatologia , Hipotermia Induzida/métodos , Hipóxia-Isquemia Encefálica/fisiopatologia , Corpos Mamilares/fisiopatologia , Substância Branca/fisiopatologia , Anisotropia , Atrofia/diagnóstico por imagem , Atrofia/patologia , Atrofia/prevenção & controle , Criança , Imagem de Tensor de Difusão , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Hipóxia-Isquemia Encefálica/patologia , Hipóxia-Isquemia Encefálica/terapia , Recém-Nascido , Masculino , Corpos Mamilares/diagnóstico por imagem , Corpos Mamilares/patologia , Memória/fisiologia , Países Baixos , Testes Neuropsicológicos , Desempenho Psicomotor/fisiologia , Estudos Retrospectivos , Instituições Acadêmicas , Estudantes , Substância Branca/diagnóstico por imagem , Substância Branca/patologiaRESUMO
BACKGROUND: Transcutaneous bilirubinometry is a widely used screening method for neonatal hyperbilirubinemia. Deviation of the transcutaneous bilirubin concentration (TcB) from the total serum bilirubin concentration (TSB) is often ascribed to biological variation between patients, but variations between TcB meters may also have a role. This study aims to provide a systematic evaluation of the inter-device reproducibility of TcB meters. MATERIALS AND METHODS: Thirteen commercially available TcB meters (JM-105 and JM-103) were evaluated in vitro on phantoms that optically mimic neonatal skin. The mimicked TcB was varied within the clinical range (0.5-181.3 µmol/L). RESULTS: Absolute differences between TcB meter outcomes increased with the measured TcB, from a difference of 5.0 µmol/L (TcB = 0.5 µmol/L phantom) up to 65.0 µmol/L (TcB = 181.3 µmol/L phantom). CONCLUSION: The inter-device reproducibility of the examined TcB meters is substantial and exceeds the specified accuracy of the device (±25.5 µmol/L), as well as the clinically used TcB safety margins (>50 µmol/L below phototherapy threshold). Healthcare providers should be well aware of this additional uncertainty in the TcB determination, especially when multiple TcB meters are employed in the same clinic. We strongly advise using a single TcB meter per patient to evaluate the TcB over time. IMPACT: Key message: The inter-device reproducibility of TcB meters is substantial and exceeds the clinically used TcB safety margins. What this study adds to existing literature: The inter-device reproducibility of transcutaneous bilirubin (TcB) meters has not been reported in the existing literature. This in vitro study systematically evaluates this inter-device reproducibility. IMPACT: This study aids in a better interpretation of the measured TcB value from a patient and is of particular importance during patient monitoring when using multiple TcB meters within the same clinical department. We strongly advise using a single TcB meter per patient to evaluate the TcB over time.
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Bilirrubina/análise , Bilirrubina/sangue , Hiperbilirrubinemia Neonatal/diagnóstico , Testes Diagnósticos de Rotina , Desenho de Equipamento , Humanos , Recém-Nascido , Doenças do Recém-Nascido , Recém-Nascido Prematuro/sangue , Monitorização Fisiológica , Triagem Neonatal/métodos , Imagens de Fantasmas , Reprodutibilidade dos Testes , Fenômenos Fisiológicos da PeleRESUMO
OBJECTIVE: To compare the effect of intervention at low vs high threshold of ventriculomegaly in preterm infants with posthemorrhagic ventricular dilatation on death or severe neurodevelopmental disability. STUDY DESIGN: This multicenter randomized controlled trial reviewed lumbar punctures initiated after either a low threshold (ventricular index of >p97 and anterior horn width of >6 mm) or high threshold (ventricular index of >p97 + 4 mm and anterior horn width of >10 mm). The composite adverse outcome was defined as death or cerebral palsy or Bayley composite cognitive/motor scores <-2 SDs at 24 months corrected age. RESULTS: Outcomes were assessed in 113 of 126 infants. The composite adverse outcome was seen in 20 of 58 infants (35%) in the low threshold group and 28 of 55 (51%) in the high threshold (P = .07). The low threshold intervention was associated with a decreased risk of an adverse outcome after correcting for gestational age, severity of intraventricular hemorrhage, and cerebellar hemorrhage (aOR, 0.24; 95% CI, 0.07-0.87; P = .03). Infants with a favorable outcome had a smaller fronto-occipital horn ratio (crude mean difference, -0.06; 95% CI, -0.09 to -0.03; P < .001) at term-equivalent age. Infants in the low threshold group with a ventriculoperitoneal shunt, had cognitive and motor scores similar to those without (P = .3 for both), whereas in the high threshold group those with a ventriculoperitoneal shunt had significantly lower scores than those without a ventriculoperitoneal shunt (P = .01 and P = .004, respectively). CONCLUSIONS: In a post hoc analysis, earlier intervention was associated with a lower odds of death or severe neurodevelopmental disability in preterm infants with progressive posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.
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Hemorragia Cerebral/complicações , Hemorragia Cerebral/cirurgia , Ventrículos Cerebrais/patologia , Doenças do Prematuro/cirurgia , Transtornos do Neurodesenvolvimento/epidemiologia , Tempo para o Tratamento , Hemorragia Cerebral/psicologia , Pré-Escolar , Estudos de Coortes , Dilatação Patológica , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/psicologia , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/prevenção & controle , Punção Espinal , Derivação VentriculoperitonealRESUMO
BACKGROUND: Literature shows that lower gestational age leads to greater delays in the auditory conduction, which suggests atypical maturation of the brainstem in normal-hearing premature newborns. Our aim is to investigate if there is a difference between the extrauterine and intrauterine maturation of the auditory system in normal-hearing newborns with a very premature (28-31 weeks) or extremely premature (<28 weeks) birth. METHODS: Results of the Automated Auditory Brainstem Response Newborn Hearing Screening Program in Dutch Neonatal Intensive Care Units and diagnostic examinations were centrally registered from 1998 to 2016. Normal-hearing newborns with a gestational age of 25-31 weeks were included. Screening results at 32-45 weeks of postmenstrual age were compared between newborns born with different gestational ages. Multiple imputation was used to predict missing screening results. Small for gestational age was defined as birth weight corrected for gestational age < -1.6 standard deviation. Descriptive and (pooled) logistic regression analyses were performed. RESULTS: 23,964 newborns with 28,754 screening results were eligible. At the same postmenstrual age, pass rates were lower when gestational age was lower in normal-hearing newborns with a very and extremely preterm birth. Pass rates of 80% could be obtained at 34-35, 32-33, and 30-32 weeks' postmenstrual age in newborns with 25, 26-27, 28-31 weeks gestational age, respectively. Small for gestational age had an additional negative effect on pass rates. CONCLUSION: Analysis of hearing screening data suggests that extrauterine maturation of the auditory system is delayed in normal-hearing newborns with a very or extremely premature birth.
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Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Audição/fisiologia , Nascimento Prematuro/fisiopatologia , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodosRESUMO
AIMS: Lidocaine is used to treat neonatal seizures refractory to other anticonvulsants. It is effective, but also associated with cardiac toxicity. Previous studies have reported on the pharmacokinetics of lidocaine in preterm and term neonates and proposed a dosing regimen for effective and safe lidocaine use. The objective of this study was to evaluate the previously developed pharmacokinetic models and dosing regimen. As a secondary objective, lidocaine effectiveness and safety were assessed. METHODS: Data from preterm neonates and (near-)term neonates with and without therapeutic hypothermia receiving lidocaine were included. Pharmacokinetic analyses were performed using non-linear mixed effects modelling. Simulations were performed to evaluate the proposed dosing regimen. Lidocaine was considered effective if no additional anticonvulsant was required and safe if no cardiac adverse events occurred. RESULTS: Data were available for 159 neonates; 50 (31.4%) preterm and 109 term neonates, of whom 49 (30.8%) were treated with therapeutic hypothermia. Lidocaine clearance increased with postmenstrual age by 0.69%/day (95% confidence interval 0.54-0.84%). During therapeutic hypothermia (33.5°C), lidocaine clearance was reduced by 21.8% (7.26%/°C, 95% confidence interval 1.63-11.2%) compared to normothermia (36.5°C). Simulations demonstrated that the proposed dosing regimen leads to adequate average lidocaine plasma concentrations. Effectiveness and safety were assessed in 92 neonates. Overall effectiveness was 53.3% (49/92) and 56.5% (13/23) for neonates receiving the proposed dosing regimen. No cardiac toxicity was observed. CONCLUSION: Lidocaine pharmacokinetics was adequately described across the entire neonatal age range. With the proposed dosing regimen, lidocaine can provide effective and safe treatment for neonatal seizures.
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Epilepsia , Hipotermia Induzida , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Humanos , Recém-Nascido , Lidocaína/uso terapêutico , Convulsões/tratamento farmacológicoRESUMO
BACKGROUND: Phenobarbital and midazolam are commonly used drugs in (near-)term neonates treated with therapeutic hypothermia for hypoxic-ischaemic encephalopathy, for sedation, and/or as anti-epileptic drug. Phenobarbital is an inducer of cytochrome P450 (CYP) 3A, while midazolam is a CYP3A substrate. Therefore, co-treatment with phenobarbital might impact midazolam clearance. OBJECTIVES: To assess pharmacokinetics and clinical anti-epileptic effectiveness of phenobarbital and midazolam in asphyxiated neonates and to develop dosing guidelines. METHODS: Data were collected in the prospective multicentre PharmaCool study. In the present study, neonates treated with therapeutic hypothermia and receiving midazolam and/or phenobarbital were included. Plasma concentrations of phenobarbital and midazolam including its metabolites were determined in blood samples drawn on days 2-5 after birth. Pharmacokinetic analyses were performed using non-linear mixed effects modelling; clinical effectiveness was defined as no use of additional anti-epileptic drugs. RESULTS: Data were available from 113 (phenobarbital) and 118 (midazolam) neonates; 68 were treated with both medications. Only clearance of 1-hydroxy midazolam was influenced by hypothermia. Phenobarbital co-administration increased midazolam clearance by a factor 2.3 (95% CI 1.9-2.9, p < 0.05). Anticonvulsant effectiveness was 65.5% for phenobarbital and 37.1% for add-on midazolam. CONCLUSIONS: Therapeutic hypothermia does not influence clearance of phenobarbital or midazolam in (near-)term neonates with hypoxic-ischaemic encephalopathy. A phenobarbital dose of 30 mg/kg is advised to reach therapeutic concentrations. Phenobarbital co-administration significantly increased midazolam clearance. Should phenobarbital be substituted by non-CYP3A inducers as first-line anticonvulsant, a 50% lower midazolam maintenance dose might be appropriate to avoid excessive exposure during the first days after birth.
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Anticonvulsivantes/farmacocinética , Asfixia Neonatal/terapia , Hipotermia Induzida , Hipóxia-Isquemia Encefálica/terapia , Midazolam/farmacocinética , Fenobarbital/farmacocinética , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/sangue , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Recém-Nascido , Masculino , Taxa de Depuração Metabólica , Midazolam/administração & dosagem , Midazolam/sangue , Fenobarbital/administração & dosagem , Fenobarbital/sangue , Guias de Prática Clínica como Assunto , Estudos ProspectivosRESUMO
OBJECTIVE: To compare the effect of early and late intervention for posthemorrhagic ventricular dilatation on additional brain injury and ventricular volume using term-equivalent age-MRI. STUDY DESIGN: In the Early vs Late Ventricular Intervention Study (ELVIS) trial, 126 preterm infants ≤34 weeks of gestation with posthemorrhagic ventricular dilatation were randomized to low-threshold (ventricular index >p97 and anterior horn width >6 mm) or high-threshold (ventricular index >p97 + 4 mm and anterior horn width >10 mm) groups. In 88 of those (80%) with a term-equivalent age-MRI, the Kidokoro Global Brain Abnormality Score and the frontal and occipital horn ratio were measured. Automatic segmentation was used for volumetric analysis. RESULTS: The total Kidokoro score of the infants in the low-threshold group (n = 44) was lower than in the high-threshold group (n = 44; median, 8 [IQR, 5-12] vs median 12 [IQR, 9-17], respectively; P < .001). More infants in the low-threshold group had a normal or mildly increased score vs more infants in the high-threshold group with a moderately or severely increased score (46% vs 11% and 89% vs 54%, respectively; P = .002). The frontal and occipital horn ratio was lower in the low-threshold group (median, 0.42 [IQR, 0.34-0.63]) than the high-threshold group (median 0.48 [IQR, 0.37-0.68], respectively; P = .001). Ventricular cerebrospinal fluid volumes could be calculated in 47 infants and were smaller in the low-threshold group (P = .03). CONCLUSIONS: More brain injury and larger ventricular volumes were demonstrated in the high vs the low-threshold group. These results support the positive effects of early intervention for posthemorrhagic ventricular dilatation. TRIAL REGISTRATION: ISRCTN43171322.
Assuntos
Lesões Encefálicas/fisiopatologia , Encéfalo/patologia , Ventrículos Cerebrais/fisiopatologia , Derivações do Líquido Cefalorraquidiano , Hemorragias Intracranianas/fisiopatologia , Encéfalo/diagnóstico por imagem , Lesões Encefálicas/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/cirurgia , Ventrículos Cerebrais/diagnóstico por imagem , Líquido Cefalorraquidiano , Dilatação , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/cirurgia , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico por imagem , Doenças do Prematuro/fisiopatologia , Doenças do Prematuro/cirurgia , Hemorragias Intracranianas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE: Morphine is a commonly used drug in encephalopathic neonates treated with therapeutic hypothermia after perinatal asphyxia. Pharmacokinetics and optimal dosing of morphine in this population are largely unknown. The objective of this study was to describe pharmacokinetics of morphine and its metabolites morphine-3-glucuronide and morphine-6-glucuronide in encephalopathic neonates treated with therapeutic hypothermia and to develop pharmacokinetics based dosing guidelines for this population. STUDY DESIGN: Term and near-term encephalopathic neonates treated with therapeutic hypothermia and receiving morphine were included in two multicenter cohort studies between 2008-2010 (SHIVER) and 2010-2014 (PharmaCool). Data were collected during hypothermia and rewarming, including blood samples for quantification of morphine and its metabolites. Parental informed consent was obtained for all participants. RESULTS: 244 patients (GA mean (sd) 39.8 (1.6) weeks, BW mean (sd) 3,428 (613) g, male 61.5%) were included. Morphine clearance was reduced under hypothermia (33.5°C) by 6.89%/°C (95% CI 5.37%/°C- 8.41%/°C, p<0.001) and metabolite clearance by 4.91%/°C (95% CI 3.53%/°C- 6.22%/°C, p<0.001) compared to normothermia (36.5°C). Simulations showed that a loading dose of 50 µg/kg followed by continuous infusion of 5 µg/kg/h resulted in morphine plasma concentrations in the desired range (between 10 and 40 µg/L) during hypothermia. CONCLUSIONS: Clearance of morphine and its metabolites in neonates is affected by therapeutic hypothermia. The regimen suggested by the simulations will be sufficient in the majority of patients. However, due to the large interpatient variability a higher dose might be necessary in individual patients to achieve the desired effect. TRIAL REGISTRATION: www.trialregister.nl NTR2529.
Assuntos
Asfixia Neonatal , Encefalopatias , Hipotermia Induzida , Morfina/administração & dosagem , Morfina/farmacocinética , Asfixia Neonatal/sangue , Asfixia Neonatal/terapia , Encefalopatias/sangue , Encefalopatias/terapia , Feminino , Humanos , Recém-Nascido , Masculino , Estudos ProspectivosRESUMO
Importance: Dexamethasone initiated after the first week of life reduces the rate of death or bronchopulmonary dysplasia (BPD) but may cause long-term adverse effects in very preterm infants. Hydrocortisone is increasingly used as an alternative, but evidence supporting its efficacy and safety is lacking. Objective: To assess the effect of hydrocortisone initiated between 7 and 14 days after birth on death or BPD in very preterm infants. Design, Setting, and Participants: Double-blind, placebo-controlled randomized trial conducted in 19 neonatal intensive care units in the Netherlands and Belgium from November 15, 2011, to December 23, 2016, among preterm infants with a gestational age of less than 30 weeks and/or birth weight of less than 1250 g who were ventilator dependent between 7 and 14 days of life, with follow-up to hospital discharge ending December 12, 2017. Interventions: Infants were randomly assigned to receive a 22-day course of systemic hydrocortisone (cumulative dose, 72.5 mg/kg) (n = 182) or placebo (n = 190). Main Outcomes and Measures: The primary outcome was a composite of death or BPD assessed at 36 weeks' postmenstrual age. Twenty-nine secondary outcomes were analyzed up to hospital discharge, including death and BPD at 36 weeks' postmenstrual age. Results: Among 372 patients randomized (mean gestational age, 26 weeks; 55% male), 371 completed the trial; parents withdrew consent for 1 child treated with hydrocortisone. Death or BPD occurred in 128 of 181 infants (70.7%) randomized to hydrocortisone and in 140 of 190 infants (73.7%) randomized to placebo (adjusted risk difference, -3.6% [95% CI, -12.7% to 5.4%]; adjusted odds ratio, 0.87 [95% CI, 0.54-1.38]; P = .54). Of 29 secondary outcomes, 8 showed significant differences, including death at 36 weeks' postmenstrual age (15.5% with hydrocortisone vs 23.7% with placebo; risk difference, -8.2% [95% CI, -16.2% to -0.1%]; odds ratio, 0.59 [95% CI, 0.35-0.995]; P = .048). Twenty-one outcomes showed nonsignificant differences, including BPD (55.2% with hydrocortisone vs 50.0% with placebo; risk difference, 5.2% [95% CI, -4.9% to 15.2%]; odds ratio, 1.24 [95% CI, 0.82-1.86]; P = .31). Hyperglycemia requiring insulin therapy was the only adverse effect reported more often in the hydrocortisone group (18.2%) than in the placebo group (7.9%). Conclusions and Relevance: Among mechanically ventilated very preterm infants, administration of hydrocortisone between 7 and 14 days after birth, compared with placebo, did not improve the composite outcome of death or BPD at 36 weeks' postmenstrual age. These findings do not support the use of hydrocortisone for this indication. Trial Registration: Netherlands National Trial Register Identifier: NTR2768.
Assuntos
Anti-Inflamatórios/administração & dosagem , Displasia Broncopulmonar/prevenção & controle , Hidrocortisona/administração & dosagem , Doenças do Prematuro/mortalidade , Recém-Nascido de muito Baixo Peso , Anti-Inflamatórios/efeitos adversos , Método Duplo-Cego , Humanos , Hidrocortisona/efeitos adversos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/prevenção & controle , Unidades de Terapia Intensiva Neonatal , Respiração Artificial , Tempo para o Tratamento , Falha de TratamentoRESUMO
BACKGROUND: Animal models suggest that neuroprotective effects of therapeutic hypothermia (TH) after perinatal asphyxia are reduced in infants with early-onset sepsis. OBJECTIVES: To assess the outcome of infants with perinatal asphyxia, neonatal encephalopathy, and TH in the presence of early-onset sepsis. METHODS: In a retrospective cohort of 1,084 infants with perinatal asphyxia and TH, the outcome of 42 infants (gestational age 36.1-42.6 weeks and birth weight 2,280-5,240 g) with proven sepsis (n = 14) and probable sepsis (n = 28) was analyzed. Death, cerebral palsy, or a delayed development at 2 years was considered an adverse outcome. RESULTS: Sepsis was caused mostly by group B streptococci (n = 17), other Gram-positive bacteria (n = 5), and Candida albicans (n = 1). Of the 42 infants, 9 (21.4%) died, and 5 (11.9%) showed impairments on follow-up. The outcome is comparable to the previously reported outcome of infants with TH without early-onset sepsis. CONCLUSION: A good outcome was reported in the majority of infants with perinatal asphyxia, TH, and early-onset sepsis. Cooling should not be withheld from these infants.