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BACKGROUND: Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. METHODS: The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18-24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. DISCUSSION: Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. TRIAL REGISTRATION: ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.
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Displasia Broncopulmonar , Doxapram , Humanos , Lactente , Recém-Nascido , Cafeína/efeitos adversos , Doxapram/efeitos adversos , Idade Gestacional , Recém-Nascido Prematuro , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Duplo-CegoRESUMO
BACKGROUND: Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. METHODS: In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. RESULTS: A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. CONCLUSIONS: Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).
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Displasia Broncopulmonar , Permeabilidade do Canal Arterial , Enterocolite Necrosante , Ibuprofeno , Conduta Expectante , Humanos , Lactente , Recém-Nascido , Displasia Broncopulmonar/etiologia , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/terapia , Ecocardiografia , Enterocolite Necrosante/etiologia , Ibuprofeno/administração & dosagem , Ibuprofeno/efeitos adversos , Ibuprofeno/uso terapêutico , Indometacina/efeitos adversos , Indometacina/uso terapêutico , Lactente Extremamente Prematuro , Recém-Nascido de Baixo Peso , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/terapiaRESUMO
INTRODUCTION: Supplemental oxygen therapy is a mainstay of modern neonatal intensive care for preterm infants. However, both insufficient and excess oxygen delivery are associated with adverse outcomes. Automated or closed loop FiO2 control has been developed to keep SpO2 within a predefined target range more effectively. METHODS: The aim of this study was to investigate the feasibility of closed loop FiO2 control by Predictive Intelligent Control of Oxygenation (PRICO) on the Fabian ventilator in maintaining SpO2 within a target range (88/89-95%) in preterm infants on different modes of invasive and noninvasive respiratory support. In two tertiary neonatal intensive care units, preterm infants with an FiO2 >0.21 were included and received an 8 h nonblinded treatment period of closed loop FiO2 control by PRICO, flanked by two 8 h control periods of routine manual control (RMC1 and RMC2). RESULTS: 32 preterm infants were included (median gestational age 26 + 5 weeks [IQR 25 + 5-27 + 6], median birthweight 828 grams [IQR 704-930]). Six patients received invasive respiratory support, while 26 received noninvasive respiratory support (18 CPAP, 4 DuoPAP, and 4 nasal IMV). The time percentage within the SpO2 target range was increased with PRICO (74.4% [IQR 67.8-78.5]) compared to RMC1 (65.8% [IQR 51.1-77.8]; p = 0.011) and RMC2 (60.6% [IQR 56.2-66.6]; p < 0.001) with an estimated median difference of 6.0% (95% CI 1.2-11.5) and 9.8% (95% CI 6.0-13.0), respectively. CONCLUSION: In preterm infants on invasive and noninvasive respiratory supports, closed loop FiO2 control by PRICO compared to RMC is feasible and superior in maintaining SpO2 within target ranges.
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Recém-Nascido Prematuro , Oxigênio , Humanos , Recém-Nascido , Lactente , Estudos de Viabilidade , Oxigenoterapia/efeitos adversos , PulmãoRESUMO
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
INTRODUCTION: Supplemental oxygen is the most important treatment for preterm born infants with established bronchopulmonary dysplasia (BPD). However, it is unknown what oxygen saturation levels are optimal to improve outcomes in infants with established BPD from 36 weeks postmenstrual age (PMA) onwards. The aim of this study is to compare the use of a higher oxygen saturation limit (≥95%) to a lower oxygen saturation limit (≥90%) after 36 weeks PMA in infants diagnosed with moderate or severe BPD. METHODS AND ANALYSIS: This non-blinded, multicentre, randomised controlled trial will recruit 198 preterm born infants with moderate or severe BPD between 36 and 38 weeks PMA. Infants will be randomised to either a lower oxygen saturation limit of 95% or to a lower limit of 90%; supplemental oxygen and/or respiratory support will be weaned based on the assigned lower oxygen saturation limit. Adherence to the oxygen saturation limit will be assessed by extracting oxygen saturation profiles from pulse oximeters regularly, until respiratory support is stopped. The primary outcome is the weight SD score at 6 months of corrected age. Secondary outcomes include anthropometrics collected at 6 and 12 months of corrected age, rehospitalisations, respiratory complaints, infant stress, parental quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: Ethical approval for the trial was obtained from the Medical Ethics Review Committee of the Erasmus University Medical Centre, Rotterdam, the Netherlands (MEC-2018-1515). Local approval for conducting the trial in the participating hospitals has been or will be obtained from the local institutional review boards. Informed consent will be obtained from the parents or legal guardians of all study participants. TRIAL REGISTRATION NUMBER: NL7149/NTR7347.
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Displasia Broncopulmonar , Displasia Broncopulmonar/terapia , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Estudos Multicêntricos como Assunto , Oxigênio , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Air-liquid interface (ALI) cultures are frequently used in lung research but require substantial cell numbers that cannot readily be obtained from patients. We explored whether organoid expansion [three-dimensional (3D)] can be used to establish ALI cultures from clinical samples with low epithelial cell numbers. Airway epithelial cells were obtained from tracheal aspirates (TA) from preterm newborns and from bronchoalveolar lavage (BAL) or bronchial tissue (BT) from adults. TA and BAL cells were 3D-expanded, whereas cells from BT were expanded in 3D and 2D. Following expansion, cells were cultured at ALI to induce differentiation. The impact of cell origin and 2D or 3D expansion was assessed with respect to 1) cellular composition, 2) response to cigarette smoke exposure, and 3) effect of Notch inhibition or IL-13 stimulation on cellular differentiation. We established well-differentiated ALI cultures from all samples. Cellular compositions (basal, ciliated, and goblet cells) were comparable. All 3D-expanded cultures showed a similar stress response following cigarette smoke exposure but differed from the 2D-expanded cultures. Higher peak levels of antioxidant genes HMOX1 and NQO1 and a more rapid return to baseline, and a lower unfolded protein response was observed after cigarette smoke exposure in 3D-derived cultures compared to 2D-derived cultures. In addition, TA- and BAL-derived cultures were less sensitive to modulation by DAPT or IL-13 than BT-derived cultures. Organoid-based expansion of clinical samples with low cell numbers, such as TA from preterm newborns is a valid method and tool to establish ALI cultures.
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Brônquios/citologia , Células Epiteliais/citologia , Organoides/citologia , Mucosa Respiratória/citologia , Fumaça/efeitos adversos , Adulto , Líquido da Lavagem Broncoalveolar/citologia , Técnicas de Cultura de Células , Diferenciação Celular/fisiologia , Células Cultivadas , Heme Oxigenase-1/metabolismo , Humanos , Recém-Nascido , Interleucina-13/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Receptores Notch/antagonistas & inibidores , Produtos do Tabaco/efeitos adversos , Resposta a Proteínas não Dobradas/efeitos dos fármacosRESUMO
BACKGROUND: Late-onset neonatal sepsis is a major complication in preterm neonates. Early identification of the type of infection could help to improve therapy and outcome depending on the suspected microorganism by tailoring antibiotic treatment to the individual patient based on the predicted organism. Results of blood cultures may take up to 2 days or may remain negative in case of clinical sepsis. Chemical biomarkers may show different patterns in response to different type of microorganisms. OBJECTIVE: The aim of this study was to develop, as a proof of concept, a simple classification tree algorithm using readily available information from biomarkers to show that biomarkers can potentially be used in discriminating in the type of infection in preterm neonates suspected of late-onset neonatal sepsis. DERIVATION COHORT: A total of 509 suspected late-onset neonatal sepsis episodes in neonates born before less than 32 weeks of gestation were analyzed. To examine model performance, 70% of the original dataset was randomly selected as a derivation cohort (n = 356; training dataset). VALIDATION COHORT: The remaining 30% of the original dataset was used as a validation cohort (n = 153; test dataset). PREDICTION MODEL: A classification tree prediction algorithm was applied to predict type of infection (defined as no/Gram-positive/Gram-negative sepsis). RESULTS: Suspected late-onset neonatal sepsis episodes were classified as no sepsis (80.8% [n = 411]), Gram-positive sepsis (13.9% [n = 71]), and Gram-negative sepsis (5.3% [n = 27]). When the derived classification tree was applied to the test cohort, the overall accuracy was 87.6% (95% CI, 81.3-92.4; p = 0.008). The classification tree demonstrates that interleukin-6 is the most important differentiating biomarker and C-reactive protein and procalcitonin help to further differentiate. CONCLUSION: We have developed and internally validated a simple, clinically relevant model to discriminate patients with different types of infection at moment of onset. Further research is needed to prospectively validate this in a larger population and assess whether adaptive antibiotic regimens are feasible.
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Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.
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Linfo-Histiocitose Hemofagocítica , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta , Hemorragia , Humanos , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , GravidezRESUMO
Over 75% of severely thrombocytopenic neonates receive platelet transfusions, though little evidence supports this practice, and only 10% develop major bleeding. In a recent randomized trial, giving platelet transfusions at a threshold platelet count of 50x109/L compared to a threshold of 25x109/L was associated with an increased risk of major bleeding or mortality. This finding highlights the need for improved and individualized guidelines on neonatal platelet transfusion, which require accurate prediction of bleeding risk. Therefore, the objective of this study was to develop a dynamic prediction model for major bleeding in thrombocytopenic preterm neonates. This model allows for calculation of bleeding risk at any time-point during the first week after the onset of severe thrombocytopenia. In this multicenter cohort study, we included neonates with a gestational age <34 weeks, admitted to a neonatal intensive care unit, who developed severe thrombocytopenia (platelet count <50x109/L). The study endpoint was major bleeding. We obtained predictions of bleeding risk using a proportional baselines landmark supermodel. Of 640 included neonates, 71 (11%) had a major bleed. We included the variables gestational age, postnatal age, intrauterine growth retardation, necrotizing enterocolitis, sepsis, platelet count and mechanical ventilation in the model. The median cross-validated c-index was 0.74 (interquartile range, 0.69-0.82). This is a promising dynamic prediction model for bleeding in this population that should be explored further in clinical studies as a potential instrument for supporting clinical decisions. The study was registered at www.clinicaltrials.gov (NCT03110887).
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Hemorragia/diagnóstico , Hemorragia/etiologia , Recém-Nascido Prematuro , Trombocitopenia/complicações , Trombocitopenia/diagnóstico , Biomarcadores , Gerenciamento Clínico , Humanos , Recém-Nascido , Recém-Nascido Prematuro/sangue , Modelos Estatísticos , Contagem de Plaquetas , Prognóstico , Reprodutibilidade dos TestesRESUMO
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.
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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
RATIONALE: Premature infants subjected to mechanical ventilation (MV) are prone to lung injury that may result in bronchopulmonary dysplasia. MV causes epithelial cell death and halts alveolar development. The exact mechanism of MV-induced epithelial cell death is unknown. OBJECTIVES: To determine the contribution of autophagy to MV-induced epithelial cell death in newborn rat lungs. METHODS: Newborn rat lungs and fetal rat lung epithelial (FRLE) cells were exposed to MV and cyclic stretch, respectively, and were then analyzed by immunoblotting and mass spectrometry for autophagy, apoptosis, and bioactive sphingolipids. MEASUREMENTS AND MAIN RESULTS: Both MV and stretch first induce autophagy (ATG 5-12 [autophagy related 5-12] and LC3B-II [microtubule-associated proteins 1A/1B light chain 3B-II] formation) followed by extrinsic apoptosis (cleaved CASP8/3 [caspase-8/3] and PARP [poly(ADP-ribose) polymerase] formation). Stretch-induced apoptosis was attenuated by inhibiting autophagy. Coimmunoprecipitation revealed that stretch promoted an interaction between LC3B and the FAS (first apoptosis signal) cell death receptor in FRLE cells. Ceramide levels, in particular C16 ceramide, were rapidly elevated in response to ventilation and stretch, and C16 ceramide treatment of FRLE cells induced autophagy and apoptosis in a temporal pattern similar to that seen with MV and stretch. SMPD1 (sphingomyelin phosphodiesterase 1) was activated by ventilation and stretch, and its inhibition prevented ceramide production, LC3B-II formation, LC3B/first apoptosis signal interaction, caspase-3 activation, and, ultimately, FLRE cell death. SMPD1 inhibition also attenuated ventilation-induced autophagy and apoptosis in newborn rats. CONCLUSIONS: Ventilation-induced ceramides promote autophagy-mediated cell death, and identifies SMPD1 as a potential therapeutic target for the treatment of ventilation-induced lung injury in newborns.
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Morte Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Recém-Nascido/fisiologia , Pulmão/metabolismo , Respiração Artificial , Esfingomielina Fosfodiesterase/metabolismo , Animais , Animais Recém-Nascidos , Humanos , Modelos Animais , RatosRESUMO
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 28 weeks. 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 (GA < 28 weeks) with an echocardiographic-confirmed PDA with a transductal diameter > 1.5 mm. Early treatment (between 24 and 72 h 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 36 weeks. 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 28 weeks, 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 36 weeks. TRIAL REGISTRATION: This trial is registered with the Dutch Trial Register NTR5479 (registered on 19 October 2015), the registry sponsored by the United States National Library of Medicine Clinicaltrials.gov NCT02884219 (registered May 2016) and the European Clinical Trials Database EudraCT 2017-001376-28 .
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Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Ibuprofeno/uso terapêutico , Lactente Extremamente Prematuro , Doenças do Prematuro/tratamento farmacológico , Conduta Expectante , Análise Custo-Benefício , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/mortalidade , Permeabilidade do Canal Arterial/cirurgia , Enterocolite Necrosante/etiologia , Humanos , Recém-Nascido , Doenças do Prematuro/mortalidade , Ligadura , Projetos de Pesquisa , Tempo para o Tratamento , Conduta Expectante/economiaRESUMO
BACKGROUND: In an experimental mouse model we showed that ceramides play a role in the pathogenesis of bronchopulmonary dysplasia (BPD) and are a potential target for therapeutic intervention. We investigated whether ceramides are detectable in tracheal aspirates (TAs) of preterm infants and differ between infants with or without BPD. METHODS: Infants born ≤ 32 weeks of gestational age in need of mechanical ventilation in the first week of life were included. TAs were obtained directly after intubation and at day 1, 3, 5, 7, and 14. Ceramide concentrations were measured by tandem mass spectrometry. At 36 weeks postmenstrual age BPD was defined as having had ≥ 28 days supplemental oxygen. RESULTS: 122 infants were included, of which 14 died and 41 developed BPD. All infants showed an increase in ceramides after the first day of intubation. The ceramide profile differed significantly between preterm infants who did and did not develop BPD. However, the ceramide profile had no additional predictive value for BPD development over GA at birth, birth weight and total days of mechanical ventilation. CONCLUSIONS: Ceramides are measurable in TAs of preterm born infants and may be an early marker for BPD development.
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Biomarcadores/metabolismo , Displasia Broncopulmonar/metabolismo , Ceramidas/metabolismo , Traqueia/metabolismo , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , MasculinoRESUMO
BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most frequent serious complication in preterm infants. We aimed to describe lung structure and ventilatory function of preterm infants with severe BPD and explored the association between early postnatal growth and these outcomes. METHODS: We included preterm infants born ≤32 weeks gestational age (GA) with severe BPD. Lung structure was assessed on chest CT with the PRAGMA-BPD scoring system and ventilatory function by polysomnography (PSG) at 6 months corrected age. Postnatal growth was assessed by weight measured at birth, and at 2 and 6 months corrected age. RESULTS: We included 49 infants (median [IQR] GA of 25.7 [24.6-26.3] weeks and mean [SD] birth weight of 760 [210] g). A 95.5% of the chest CT scans showed architectural distortion of the lung, and an oxygen desaturation index (ODI) >5 was found in 74% of the infants. An increase in GA of 1 week was associated with higher total and normal lung volume (ß coefficient [95% CI]: 1.86 [0.15, 3.57] and 2.03 [0.41, 3.65]), less hypoattenuation (-4.3 [-7.70, -0.90]%) and lower ODI (-36.7 [-64.2, -9.10]%). Higher weight at 6 months was independently associated with higher total and normal lung volume, and with less severe desaturations. Increased weight gain between 2 and 6 months of corrected age was associated with less severe desaturations during sleep (ß coefficient [95% CI]: 2.09 [0.49, 3.70]). CONCLUSION: Most preterm infants with severe BPD have structural lung abnormalities and impaired ventilatory function early in life, partly explained by birth characteristics and infant growth.
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Displasia Broncopulmonar/fisiopatologia , Recém-Nascido Prematuro/fisiologia , Pulmão/anormalidades , Pulmão/fisiopatologia , Ventilação Pulmonar , Peso ao Nascer , Displasia Broncopulmonar/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Pulmão/diagnóstico por imagem , Masculino , Polissonografia , Volume de Ventilação Pulmonar , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Since 2010, the European Resuscitation Council (ERC) guidelines advise oxygen saturation (SpO2) targets for the first 10 min of resuscitation after birth. Unfortunately, the control of SpO2 in newborn infants is difficult. AIM: To determine to what extent SpO2 levels match the ERC targets during the resuscitation of very preterm infants, and how well the SpO2 is kept within the high and low limits until the infants are transported to the NICU. METHODS: In a single-centre observational study, the SpO2 and fraction of inspired oxygen (FiO2) were collected during the resuscitation of very preterm infants with a gestational age (GA)≤ 30 weeks. RESULTS: A total of 78 infants were included [median (IQR): GA 27(4)/7 (26-28(6)/7) weeks, birth weight 945 g (780-1140)]. During the initial 10 min after birth, large variations in SpO2 were observed with deviations above the target [median (IQR)] of 4.4% SpO2 (1.4-6.5), and below the target of 8.2% SpO2 (2.8-16.0). After the first 10 min, the SpO2 levels were respectively above and below the limit for 11% (0-27) and 8% (0-23) of the time. CONCLUSION: During the resuscitation of very preterm infants, large deviations of the SpO2 from the ERC targets are observed. During the first minutes of resuscitation the deviations were likely caused by an inability to control the SpO2, whereas later deviations were due to weaning, pauses in respiratory support (i.e. intubation) and over exposure to oxygen. Changing the SpO2 targets to a target range that depicts the acceptable deviation might be helpful in providing better respiratory support.
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Lactente Extremamente Prematuro/sangue , Doenças do Prematuro , Oximetria , Oxigênio/sangue , Ressuscitação , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/epidemiologia , Doenças do Prematuro/terapia , Masculino , Monitorização Fisiológica/métodos , Países Baixos/epidemiologia , Avaliação de Processos e Resultados em Cuidados de Saúde , Oximetria/métodos , Oximetria/normas , Ressuscitação/métodos , Ressuscitação/estatística & dados numéricos , Tempo para o TratamentoRESUMO
AIM: To evaluate the practical feasibility for nurses working with neurally adjusted ventilatory assist (NAVA) and assess patient comfort and safety when NAVA is initiated. BACKGROUND: NAVA is a relatively new mode of ventilation. Its application in neonates and children has been widely documented. However, its practical feasibility from a nursing point of view as well as its safety and comfort in these populations compared with conventional modes of ventilation has not been described. DESIGN: A prospective, observational crossover pilot study. METHOD: NAVA was compared with the conventional mode of ventilation for 3 h each, and practical feasibility, patient comfort level and safety were assessed. RESULTS: Twenty-one neonates and children were enrolled into the study. There were no reported adverse events. In most patients, the NAVA catheter was placed too shallow, as measured by the distances from the nose, ear, xiphisternum (NEX) method, according to the manufacturer's instructions. Accurate placement was confirmed by visual inspection of the NAVA positioning window. Patients' comfort did not differ between the conventional mode and NAVA. CONCLUSIONS: NAVA is feasible, once an accurate signal of the electrical activity of the diaphragm is achieved and seems safe and well tolerated in both neonates and children. Nurses need to gain experience in placing the NAVA catheter and practical recommendations are given. RELEVANCE TO CLINICAL PRACTICE: NAVA is a promising new mode of ventilation. This article contributes to an increasing body of evidence that NAVA is feasible in neonates and children. There are practical considerations when NAVA is applied in these patient-groups.
Assuntos
Suporte Ventilatório Interativo , Criança , Sedação Consciente , Estudos Cross-Over , Estudos de Viabilidade , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Suporte Ventilatório Interativo/enfermagem , Masculino , Segurança do Paciente , Projetos Piloto , Estudos ProspectivosRESUMO
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.
Assuntos
Displasia Broncopulmonar/prevenção & controle , Glucocorticoides/administração & dosagem , Hidrocortisona/administração & dosagem , Recém-Nascido Prematuro , Bélgica/epidemiologia , Displasia Broncopulmonar/epidemiologia , Displasia Broncopulmonar/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Vias de Administração de Medicamentos , Seguimentos , Glucocorticoides/farmacocinética , Humanos , Hidrocortisona/farmacocinética , Incidência , Mortalidade Infantil/tendências , Recém-Nascido , Países Baixos/epidemiologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Congenital acute myeloid leukemia (AML), and especially AML-M6 is a rare disease with a poor prognosis. Moreover, reports of treatment outcome of congenital AML-M6 in premature infants are not available. We report the first treated case of congenital AML-M6 in a premature girl, who received a full AML protocol. She presented with blueberry-muffin spots, anemia, high white blood cell count, and serious cardiopulmonary distress. Peripheral blood smears showed AML-M6 blasts. After treatment with a sequential low-dose cytarabine after birth and full-dose AML treatment according to the MRC-12 protocol at the age of 2 months, she now is in continuous complete remission for 4 years.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Doenças do Prematuro/tratamento farmacológico , Recém-Nascido Prematuro , Leucemia Mieloide Aguda/tratamento farmacológico , Feminino , Humanos , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/patologia , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/patologia , Indução de RemissãoRESUMO
On MRI at 35 weeks of a boy born at 25 weeks, focal disorganization of the cortex was observed near a frontal venous infarct developed in the first week. Disruption of the final steps of cell migration, injury to the subplate and/or disruption of corticospinal axons are possible mechanisms behind it. Preterms with white matter lesions at or below 25 weeks postconceptional age should be scrutinized for cortical dysplasia.
Assuntos
Córtex Cerebral/anormalidades , Infarto Cerebral/etiologia , Córtex Cerebral/patologia , Infarto Cerebral/diagnóstico , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Imageamento por Ressonância Magnética , Masculino , Hemorragia Subaracnóidea/diagnóstico , Hemorragia Subaracnóidea/diagnóstico por imagem , UltrassonografiaRESUMO
Idiopathic infantile arterial calcification (IIAC) is a rare disease characterised by extensive depositions of hydroxyapatite in the internal elastic lamina of medium-sized and large arteries, frequently accompanied by periarticular calcifications. We report on three patients with various presenting signs and symptoms. Diagnostic imaging techniques and therapy with bisphosphonates will be discussed. For the first time long-term follow-up of up to 25 years will be reported.