Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Lung diseases associated with immaturity may contribute to the delay in the development of the newborn preterm. The oral feeding may suffer because they spend a lot of energy function in the disorder of the respiratory muscles and the lack of coordination between sucking / swallowing / breathing. The objective of this research was to compare the effects of increased technical expiratory flow slow in relation to the technical manual chest vibration on cardiorespiratory parameters and food performance of newborn preterm with lung disease. Babies who fulfilled the inclusion criteria and that those responsible have allowed their participation, were allocated at random to one of the groups (group 1 - increased expiratory flow slow; group 2 - manual chest vibration). We collected the cardiorespiratory parameters (RR, HR, SpO2) five minutes prior to physical therapy after 5 minutes started oral feeding, and 5 minutes after the end of the food supply. The physical therapy continued until obtaining the full orally, twice daily. Oral feeding performance was evaluated using the variables proficiency, throughput and performance oral feeding, the first oral feeding, and the days to reach full orally. The expiratory flow slow increase technique provided greater cardiorespiratory stability in children with respiratory distress syndrome and bronchopulmonary dysplasia in FR parameter (p=0.0029 and p=0.0344, respectively). In comparison within the group, for children with hyaline membrane disease subjected to vibration there was a significant increase in RR at the end of feeding (p=0.008). Submitted to the increase in technical expiratory flow slow the RF remained stable with significant increase in SpO2 (p=0.001).In the analysis of food performance, it was observed that physical therapy technique did not influence the variables proficiency, throughput and oral feeding performance in the first orally, and did not influence the dietary transition. We conclude that, although the technique of increased expiratory flow has not shown effects on oral feeding performance, presented benefits to newborn preterm, compared to vibration because it provided greater cardiorespiratory stability. / Doenças pulmonares associadas à imaturidade podem contribuir para o atraso no desenvolvimento do recém-nascido pré-termo. A alimentação via oral pode ser prejudicada, pois eles gastam muita energia em função da desordem da musculatura respiratória e a falta de coordenação entre sucção/deglutição/respiração. O objetivo dessa pesquisa foi comparar os efeitos da técnica de aumento do fluxo expiratório lento, em relação à técnica vibração manual torácica, sobre os parâmetros cardiorrespiratórios e a performance alimentar de recém-nascidos pré-termo com doença pulmonar. Os bebês que se enquadraram nos critérios de inclusão e que os responsáveis permitiram sua participação, foram alocados por sorteio para um dos grupos (grupo 1 aumento do fluxo expiratório lento; grupo 2 vibração manual torácica). Foram coletados os parâmetros cardiorrespiratórios (FR, FC, SatO2) 5 minutos antes da fisioterapia, após 5 minutos de iniciada alimentação via oral, e 5 minutos após término da oferta alimentar. O atendimento fisioterapêutico continuou até a obtenção da via oral plena, duas vezes ao dia. A performance alimentar oral foi avaliada através das variáveis proficiência, taxa de transferência e desempenho alimentar oral, na primeira mamada oral, e pelos dias para obtenção da via oral plena. A técnica de aumento do fluxo expiratório lento proporcionou maior estabilidade cardiorrespiratória nas crianças com doença da membrana hialina e displasia broncopulmonar no parâmetro de FR (p=0,0029 e p=0,0344, respectivamente). Na comparação dentro do próprio grupo, para as crianças com doença da membrana hialina submetidas à vibração houve aumento significativo da FR, ao final da mamada (p=0,008). Nas submetidas à técnica de aumento do fluxo expiratório lento a FR manteve-se estável com elevação significativa na SatO2 (p=0,001). Na análise da performance alimentar, observou-se que a técnica de fisioterapia não influenciou as variáveis proficiência, taxa de transferência e desempenho alimentar oral, na primeira via oral, assim como não influenciou a transição alimentar. Conclui-se que, embora a técnica de aumento do fluxo expiratório não tenha mostrado efeito sobre a performance alimentar oral, apresentou benefícios ao recém-nascido pré-termo, quando comparada à vibração, pois proporcionou maior estabilidade cardiorrespiratória.

Orientadores: Jose Dirceu Ribeiro, Maria Aparecida Marques dos Santos Mezzacappa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-07T08:58:42Z (GMT). No. of bitstreams: 1 Mendes_ThaisdeBarros_M.pdf: 697160 bytes, checksum: 683a02d47dfa9c24c4f1e7ea7b12f590 (MD5) Previous issue date: 2006 / Resumo: A doença pelo refluxo gastroesofágico (DRGE) é a enfermidade esofágica mais comum no período neonatal, e tem sido implicada como um fator contribuinte para as doenças respiratórias. Entretanto, muitos de seus aspectos são controversos e não são adequadamente conhecidos em recém-nascidos prematuros. A displasia broncopulmonar (DBP) é a doença pulmonar crônica mais freqüente em recém-nascidos de muito baixo peso (RNMBP). Em virtude da escassez de informações sobre o diagnóstico de DRGE em pacientes com DBP e dadas às conseqüências sobre a sua morbidade, pareceu-nos importante conhecer os fatores de risco para a associação, podendo colaborar com a melhora da qualidade da assistência prestada. Este estudo teve o objetivo de conhecer os fatores de risco para a DRGE em RNMBP com DBP, investigados por meio da monitorização prolongada do pH esofágico distal. Verificar se o corticóide pré-natal é fator de risco para a DRGE, bem como identificar os fatores de risco demográficos do RN, definir os fatores de risco referentes à evolução pós-natal do RN e determinar se alguns dos procedimentos e os medicamentos administrados ao RN são fatores de risco para a DRGE. Foi realizado um estudo observacional, retrospectivo, de caso-controle. O diagnóstico de DRGE foi estabelecido pelas manifestações clínicas e pelo índice de refluxo = 10%. Foram estudados todos os RN com DBP que receberam diagnóstico de DRGE por meio da monitorização do pH esofágico, em condições padronizadas, no período janeiro de 2001 a outubro de 2005, no Centro de Atenção Integral à Saúde da Mulher. O tamanho da amostra foi de 23 casos e igual número de controles, não emparelhados, que foram comparados quanto à idade gestacional, peso ao nascimento, gênero, uso de corticóide pré-natal, tempo de ventilação assistida, oxigenoterapia, tempo de uso de sonda gástrica, xantinas, idade pós-conceptual e peso à monitorização do pH esofágico. Para a análise estatística foram empregados, inicialmente, os testes de Qui-quadrado e o teste Exato de Fisher, para as variáveis categóricas e para as variáveis numéricas a comparação entre os grupos foi realizada pelo teste U de Mann-Whitney. Em seguida, para analisar a influência dos fatores de risco para a DRGE foi realizada análise por regressão logística univariada e múltipla para estabelecer o odds-ratio (OR) e o seu respectivo intervalo de confiança de 95% (IC). Foram considerados como significativos os valores de p< 0,05. Os dois grupos (com e sem DRGE) não apresentaram diferenças significativas em relação às variáveis demográficas, as de evolução pós-natal, ao uso de corticóide pré e pós-natal, bem como ao tempo de uso de cafeína, ventilação mecânica e oxigenoterapia. Entretanto, as variáveis: intolerância alimentar (OR 6,55; IC 1,05 - 40,8) e tempo de uso de sonda gástrica (OR 1,67; IC 1,11 - 2,51) associaram-se independentemente à DRGE. A maior idade pós-conceptual ao exame (OR 0,02; IC <0,001 - 0,38) foi identificada como fator protetor para a DRGE. O presente estudo permite inferir que o tempo prolongado de uso de sonda gástrica e a ocorrência de intolerância alimentar aumentam a probabilidade para a DRGE, em RNPT menores de 1500 gramas com DBP. Já a maior idade pós-conceptual ao exame diminui a chance para a DRGE. Estes achados merecem atenção e outros estudos, para maximizar a correlação dos fatores de risco para a DRGE em neonatos com DBP / Abstract: Gastroesophageal reflux disease (GERD) is the most common illness in neonatal period, and is considered an associated factor for respiratory diseases. However, several aspects of GERD are controversy and not appropriately known in premature. Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in very low birth weight (VLBW) infants. Due to shortage of information¿s about diagnosis of GERD in patients with BPD and considering the consequences about his morbidity, seems to us important to know the risk factors for the association, be able to collaborate with the improvement of quality of treatment. The objective of this study was to determine the risk factors for GERD in extremely low birth weight infants with BPD. A retrospective case-control study was realized, including 23 patients and 23 control subjects who were diagnosed by clinical manifestations and 24 hours esophageal pH monitoring presenting reflux index = 10%. All newborn with BPD were studied from January 2001 to October 2005 at the Center for Women¿s Integral Health Care. Cases and controls were compared for gestational age, birth weight, gender, antenatal steroid use, assisted ventilation time, oxygen therapy and time of feed tube use, xanthine, post conceptual age and weight on esophageal pH monitoring. For the statistic analysis were utilized, initially, the square¿ test and the Fisher¿s exact test for the numerical variables, and Mann-Whitney¿s test for category variables. Multiple logistic regression was made for to establish odds-ratio (OR) with confidence interval of 95% (CI). Were considered significant p< 0.05. Both groups (with and without GERD) didn¿t show significant differences on variables: demographics, postnatal evolution, prenatal and postnatal steroids use, caffeine utilization, mechanical ventilation and oxygen therapy. The variables feeding intolerance (OR 6.55; CI 1.05; 40.8) and time of gastric tube use (OR 1.67; CI 1.11; 2.51) showed be risk factors for GERD. The major post conceptual age on esophageal Ph monitoring (OR 0.02; CI <0.001; 0.38) showed be protector factor for GERD. The obtained data showed that a prolonged gastric tubes use and the feeding intolerance increase probability for GERD. While the major post conceptual age on esophageal pH monitoring decrease likelihood for GERD in premature neonates with BPD / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introduction: The Bronchopulmonary dysplasia (BPD) is a major chronic respiratory condition found in newborn preterm infants (PTI) of gestational age and reduced birth weight associated with immaturity and diminished alveolarization. The transition from tube to oral feeding in children who develop dysplasia during the neonatal period is difficult to manage, requiring special attention when the oral starts. Objective: To evaluate the repercussion of DBP on the feeding readiness and the feeding performance of PTI. Methods: The sample was consisted to 53 children assigned to a group with BPD (G1=14) and a group without BPD (G2=39). In the first oral feed was performed the evaluation of readiness, or oral feeding ability, by the Fujinaga (2005) and Lau & Smith (2011) protocols. The feed performance was evaluated through proficiency, transfer rate of milk and feed performance as well the occurrence of signs of stress in the first feeding orally. Was also evaluated the time to attainment of full orally. Results: Presence of oral skill to begin oral feeding was observed in 64,3% and 21,4% of PTI with BPD, according to the protocols of Fujinaga (2005) and Lau & Smith (2011), respectively. In the group without BPD, 69,2% and 48,7% had skill, according Fujinaga (2005) and Lau & Smith (2011), respectively. Regarding food performance, the PTI with BPD showed worse results, both as to the proficiency and performance feed (p<0,05), as well as in relation to signs of stress. The feeding transition occurred at 12,9 (±10,5) days in children without BPD and 26,8 (±13,8) days in those with BPD (p=0,0002). Conclusion: At the time of release of oral feed, most preterm infants with BPD was not able to feed, according to the protocol of Lau & Smith (2011). As consequence the dysplasic children showed lower feeding performance and greater occurrence of signs of stress in first oral feed. The time required to attainment of full oral feeding was significantly higher in PTI with BPD. / Introdução: A displasia broncopulmonar (DBP) é uma importante condição respiratória crônica encontrada em recém-nascidos pré-termo (RNPT) de idade gestacional e peso ao nascimento reduzido, associada com a imaturidade pulmonar e alveolarização diminuída. A transição alimentar da sonda gástrica para via oral em crianças que desenvolvem displasia durante o período neonatal é de difícil manejo, necessitando de uma atenção especial no momento em que a via oral é iniciada. Objetivo: Avaliar a repercussão da DBP sobre a prontidão e a performance alimentar de RNPT. Métodos: A amostra foi constituída por 53 crianças distribuídas em um grupo com DBP (G1=14) e um grupo sem DBP (G2=39). Na primeira oferta alimentar por via oral foi realizada a avaliação da prontidão ou habilidade de alimentação oral, através dos protocolos de Fujinaga (2005) e Lau & Smith (2011). A performance alimentar foi avaliada através da proficiência, da taxa de transferência e do desempenho alimentar, bem como da ocorrência de sinais de estresse na primeira mamada por via oral. Foi também avaliado o tempo necessário para obtenção da via oral plena. Resultados: Presença de habilidade oral para iniciar a alimentação por via oral foi observada em 64,3% e 21,4% dos RNPT com DBP, segundo os protocolos de Fujinaga (2005) e Lau & Smith (2011), respectivamente. No grupo sem DBP, 69,2% e 48,7% apresentavam habilidade, de acordo com Fuginaga (2005) e Lau & Smith (2011), respectivamente. Em relação à performance alimentar, os RNPT com DBP apresentaram piores resultados, tanto para a proficiência quanto para o desempenho alimentar (p<0,05), assim como em relação a presença de sinais de estresse. A transição alimentar ocorreu em 12,9 (±10,5) dias nas crianças sem DBP e em 26,8 (±13,8) dias nos com DBP (p=0,0002). Conclusão: No momento da liberação da via oral, a maioria dos prematuros com DBP não estava apto para a mamada, segundo o protocolo de Lau & Smith (2011). Como consequência, as crianças displásicas apresentaram pior performance alimentar e maior ocorrência de sinais de estresse, na primeira mamada por via oral. O tempo necessário para obtenção da via oral plena foi significativamente maior nos prematuros com DBP.

Abstract Deficiency of pulmonary surfactant is the main cause of respiratory distress syndrome (RDS) in premature newborn infants, which is often complicated by chronic lung disease (CLD). Preterm birth is often associated with intra-amniotic infection (IUI), which is characterized by increased proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), in the amniotic fluid. In very preterm birth due to IUI, the incidence of RDS is decreased, while the incidence of CLD is increased. Maternal glucocorticoids are used in imminent preterm birth to prevent RDS. This study was designed to clarify the contrasting association of these perinatal pulmonary diseases with IUI and the pathogenesis of these lung diseases using an in vitro rabbit model. IL-1 increased the expression of surfactant protein (SP)-A and SP-B in very immature lung. Contrariwise, in transitional and mature fetal lung as well as in newborn lung, IL-1 additively with TNF-α decreased the expression of SP-B and SP-C. Bacterial lipopolysaccharide (LPS) decreased SP-A, -B and -C mRNAs in mature fetal and newborn lung, but had no effect on SP expression in immature lung. Interferon-γ (IFN-γ) had no effect on SP expression at any gestational age, but it modified the effects of the other cytokines. Dexamethasone (Dx) and IL-1 in combination additively increased SP-A and SP-B mRNAs in immature lung. Dx abolished the inhibitory effect of IL-1 on SP-B and SP-C in mature lung. Dx and IL-1 together tended to stabilize SP mRNAs. The present findings provide additional evidence of the role of the transcription factors nuclear factor-κB (NF-κB) and C/CAAT enhancer-binding protein δ (C/EBPδ) in the upregulation of SP-A by IL-1 in immature lung. Proinflammatory cytokines profoundly influence the expression of surfactant proteins in a manner that is strictly dependent on the length of gestation. The present findings help to explain the differences in the incidence of RDS and CLD in preterm births caused by IUI, and they may clarify further the role of surfactant in the pathogenesesis of lung diseases in neonatal infants. / Tiivistelmä Keuhkosurfaktantin puute aiheuttaa ennenaikaisesti syntyville keskosille vastasyntyneen hengitysvaikeusoireyhtymää eli RDS-tautia (Respiratory Distress Syndrome). Toinen keskosilla esiintyvä keuhkosairaus on krooninen keuhkosairaus eli CLD (Chronic Lung Disease). Glukokortikoideja käytetään hoitona ennenaikaisen synnytyksen uhatessa, koska niiden tiedetään vähentävän RDS-taudin riskiä. Kohdunsisäinen infektio on huomattava ennenaikaisen synnytyksen aiheuttaja. Infektiossa tulehduksen välittäjäaineet, kuten sytokiinit interleukiini-1 (IL-1) ja tuumorinekroositekijä alfa (TNF-α) lisääntyvät lapsivedessä. Infektiosta aiheutunut ennenaikainen synnytys vähentää RDS-taudin ilmaantumista pienille keskosille ja toisaalta lisää kroonisen keuhkosairauden riskiä. Tutkimuksen oli tavoitteena selvittää, miksi RDS ja CLD ilmaantuvat eriävästi infektion vuoksi ennenaikaisesti syntyneille vauvoille. Viljelemällä eri-ikäisten kanin sikiöiden sekä vastasyntyneiden kanin poikasten keuhkon kappaleita tutkittiin tulehduksen välittäjäaineiden sekä anti-inflammatorisen glukokortikoidin (deksametasonin) vaikutusta surfaktantin toiminnalle tarpeellisten surfaktanttiproteiinien (SP) ilmentymiseen. IL-1 lisäsi SP-A:n ja SP-B:n ilmentymistä erittäin epäkypsässä kanin sikiön keuhkossa. Toisaalta IL-1 ja TNF-α vähensivät SP-B:n ja SP-C:n ilmentymistä kypsemmässä sikiön sekä vastasyntyneen kanin keuhkossa. Interferoni-gamma (IFN-γ) ei vaikuttanut surfaktanttiproteiinien ilmentymiseen missään gestaatioiässä, mutta se muunsi muiden sytokiinien surfaktanttivaikutusta. Gram-negatiivisten bakteerien soluseinän tuote, lipopolysakkaridi (LPS) vähensi SP-A:n, SP-B:n ja SP-C:n ilmentymistä kypsässä kanin sikiön ja vastasyntyneen kanin keuhkossa. IL-1:llä ja deksametasonilla oli positiivinen yhteisvaikutus surfaktanttiproteiinien ilmentymiseen. Tämän surfaktanttiproteiineja lisäävän vaikutuksen mekanismiksi havaittiin pääasiallisesti lisääntynyt mRNA:n stabiliteetti. Lisäksi tutkimus antaa lisätietoa kahden transkriptiofaktorin, NF-κB:n (nuclear factor kappa B) ja C/EBPγ:n (C/CAAT enhancer binding protein delta), osuudesta IL-1:n aiheuttamassa SP-A:n ilmentymisen lisääntymisessä. Sytokiinien vaikutukset surfaktanttiproteiinien ilmentymiseen ovat riippuvaisia gestaatioiästä. Tutkimuksen löydökset auttavat ymmärtämään RDS:n ja CLD:n vastakohtaista esiintymismäärää keskosilla, joiden ennenaikainen synnytys on aiheutunut kohdunsisäisestä tulehduksesta. Edelleen tutkimus selittää glukokortikoidien positiivista vaikutusta hengitysvajaukseen johtavassa keuhkotulehduksessa.

Abstract The aim of the study was to evaluate the efficacy and safety of antenatal and postnatal corticosteroids in the prevention for mortality and acute and long-term morbidity in preterm infants. Altogether 109 eligible preterm infants participated in a randomized, multi-center, double-blinded controlled trial studying the efficacy of early dexamethasone (DX) treatment. The infants received either four doses of DX or placebo. DX treatment did not have a detectable influence on survival without bronchopulmonary dysplasia (BPD), severe intracranial hemorrhage, or periventricular leukomalacia. In a meta-analysis of 15 trials, we found that early prolonged DX treatment (> 96 h, n = 1594 infants) decreased the risk of BPD (RR 0.72 95% CI 0.61–0.87), whereas early short DX course did not (n = 1069 infants). However, prolonged DX increased the risk of gastrointestinal (GI) complications (RR 1.59 95% CI 1.02–2.46). Fifty-one very preterm infants participated in a randomized placebo-controlled trial studying early hydrocortisone (HC) started before 36 hours of age and continued for 10 days. The basal and stimulated serum cortisol levels were measured before the intervention. The study was interrupted because of GI perforations in the HC group. HC decreased the risk of patent ductus arteriosus. HC-treated infants with serum cortisol concentrations above the median had a high risk of GI perforation. HC increased survival without BPD among infants with low endogenous cortisol levels. Altogether 45 surviving infants were enrolled in the follow-up of the early HC trial at 2 years of age. None of the study patients had died after discharge. There was no difference in the recorded rehospitalization rate, growth characteristics, or neurological development between HC and placebo-treated children. Altogether 249 women pregnant at less than 34.0 gestational weeks participated in a randomized trial studying the efficacy of a single additional dose of betamethasone (BM). All of the 159 infants in the BM group and 167 in the placebo group were born before 36 weeks of gestation. Intact survival was comparable between the BM and placebo groups, whereas the need for surfactant therapy in RDS was increased in the BM group. According to a post hoc analysis of 206 infants delivered within 1–24 hours, the BM booster tended to increase the risk of RDS and to decrease intact survival.

La dysplasie broncho-pulmonaire (DBP), complication fréquente de la prématurité, atteint 30% des nouveau-nés de faible poids de naissance. L’hypertension artérielle pulmonaire persistante du nouveau-né (HTAPP), associé ou non à la DBP, résulte d’une mauvaise adaptation à la vie extra-utérine et survient dans diverses situations pathologiques (prématurité, sepsis, inhalation de méconium, hernie diaphragmatique congénitale…). Ces 2 pathologies sont grevées d’une morbidité et d’une mortalité importante en période périnatale. En effet, certaines situations d’HTAPP ou de DBP sévères restent réfractaires aux thérapeutiques actuelles.Les acides gras polyinsaturés oméga 3 (AGPI ω-3) sont des nutriments aux propriétés bénéfiques sur le système circulatoire et pulmonaire, mais également sur le développement fœtal, démontrés par de nombreuses études expérimentales et cliniques. La déhydroépiandrostérone (DHEA) est une hormone stéroïdienne dont le taux de sécrétion chez l’homme diminue avec l’âge. Des études récentes ont démontré un effet cardio-protecteur mais également un effet vasodilatateur pulmonaire et préventif de lésions de DBP dans des modèles expérimentaux.Les buts de notre travail étaient 1) d’étudier l’effet d’une supplémentation en AGPI ω-3 dans un modèle expérimental de DBP induite par hyperoxie chez le raton, 2) d’étudier l’effet circulatoire d’injection d’AGPI ω-3 (in vivo) dans un modèle d’étude de la circulation pulmonaire chez le fœtus de brebis chroniquement instrumenté, et d’étudier les mécanismes d’action AGPI ω-3 (anneaux vasculaires isolés) , enfin 3) d’étudier l’effet circulatoire de la DHEA (in vivo) dans le modèle de fœtus de brebis et d’étudier les mécanismes d’actions de la DHEA sur la circulation pulmonaire fœtale (in vivo)._x000D_Nous avons démontré que la supplémentation par voie orale en AGPI ω-3 de rates gestantes à la fin de la gestation et après la naissance permettait de prévenir, chez les ratons nouveau-nés, les lésions de DBP induites par une exposition chronique à l’hyperoxie. Ces lésions étaient retrouvées dans les groupes contrôles (eau et AGPI ω-6). Cette étude n’avait pas retrouvée d’effet bénéfique des AGPI ω-3 sur le remodelage vasculaire induit.L’injection d’acide eicosapentaènoique (EPA) chez le fœtus de brebis a révélé un effet vasodilatateur pulmonaire puissant avec une baisse significative et prolongée des résistances vasculaires pulmonaires (RVP), en comparaison à l’injection d’acide docosahéxaènoique (DHA) ou de l’excipient (faible dose d’éthanol). L’effet vasorelaxant de l’EPA sur des anneaux isolés pré-contractés était plus important que celui du DHA à dose équivalente, et il était dose- et endothélium-dépendent. Enfin, cet effet impliquait la voie de production du NO puisqu’il était diminué lors du traitement des anneaux par le L-Nitro-Arginine (LNA), inhibant la NO synthase.L’étude de perfusion en bolus de DHEA dans le lit pulmonaire vasculaire chez le fœtus de brebis instrumenté mettait en évidence un effet vasodilatateur bref. Cet effet était dose-dépendant avec une baisse plus prononcée des RVP et une durée plus importante pour des doses de DHEA plus importantes. Enfin l’étude des mécanismes d’action retrouvait une inhibition de l’effet de la DHEA par le LNA, démontrant une action vasodilatatrice par activation de production du NO.L’ensemble de ces travaux permet de suggérer que les AGPI ω-3 représentent des nutriments intéressants en période périnatale (grossesse, allaitement et per os), notamment en traitement préventif dans les situations à risque de DBP, ou curatif en cas d’HTAPP. La DHEA reste une piste dans le traitement de l’HTAP, mais semble pour l’instant plus difficile à instaurer en clinique humaine. / Bronchopulmonary dysplasia (BPD), a common complication of prematurity, reached in 30% of newborns with very low birth weight. Persistent pulmonary hypertension of the newborn (PPHN), with or without BPD, results in poor adaptation to extrauterine life and occurs in various pathological conditions such as prematurity, sepsis, inhaled meconium, or diaphragmatic hernia Congenital. The mortality and morbidities of these two diseases are high in the perinatal period. Severe PPHN or BPD are refractory to current treatment.Polyunsaturated fatty acids omega-3 (ω-3 PUFA) are nutrients with beneficial properties on the circulatory and pulmonary system, but also on fetal development, demonstrated by many experimental and clinical studies. Dehydroepiandrosterone (DHEA) is a steroid hormone whose secretion levels in humans decreases with age. Recent studies have demonstrated a cardio-protective effect of diet DHEA supplementation but also a pulmonary vasodilator and preventive effect of DBP injury in experimental models.The aims of our study were : 1) to study the effect of PUFA ω-3 supplementation in an experimental model of hyperoxia-induced DBP in pups; 2) to study effect on pulmonary circulation of infusion of ω-3 PUFAs (in vivo) in model of chronically instrumented fetal sheep, and to analyze the mechanisms of action of ω-3 PUFA (isolated vascular rings); and finally 3) to study the in vivo effect of DHEA in fetal pulmonary circulation in the same model of fetal sheep and to understand the mechanisms of action of DHEA._x000D_We have demonstrated that supplementation with diet PUFA ω-3 on pregnant rats at the end of gestation and after birth prevent BPD injuries induced by chronic exposure to hyperoxia in pups. These lesions were found in the control groups (water and ω-6 PUFA). ω-3 PUFA supplementation did not prevent vascular remodeling.Infusion of eicosapentaenoic acid (EPA) in sheep fetus showed a potent pulmonary vasodilator effect as compared to docosahexaenoic acid (DHA) or excipient (low dose of ethanol). Vasorelaxant effect of EPA on pre-contracted isolated rings was more important than DHA at equivalent dose, and was dose- and endothelium-dependent. This effect involves NO production.Bolus DHEA perfusion in the pulmonary vascular bed study on instrumented fetal sheep highlighted an acute vasodilator effect. This effect was dose-dependent with a more pronounced and sustained decrease in PVR at highest doses of DHEA. Finally, mechanisms of action study found an inhibition of the effect of DHEA by the LNA, indicating that DHEA-induced vasodilation is NO dependant.Taken together, our results suggest that supplementation with ω-3 PUFAs and DHEA within the perinatal period may prevent BPD and PPHN in high risk conditions including preterm birth, premature rupture of the membrane or intrauterine growth restriction.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease and one of the most severe complications that develop in premature infants following mechanical ventilation, exposure to supplemental oxygen, and inflammation. The hallmarks of the lung pathology are arrested lung development, including fewer and larger alveoli with less septation, thickening of alveolar septa, and impaired development of the capillary network. BPD is associated with increased mortality, respiratory morbidity, neurodevelopmental impairment, and increased healthcare costs. Significant advancements in neonatology in the last several decades, including antenatal steroids and exogenous surfactant replacement therapy, more gentle ventilation methods, and judicious oxygen use, have allowed for the survival of more preterm infants. However, the incidence of BPD still remains high and currently, there is no cure for the disease. Novel effective interventions at this stage of life are of exceptional value. Considering their great potential in promoting tissue regeneration and modulating inflammation, mesenchymal stromal cells (MSCs) represent a promising avenue for treating several disorders, including BPD. Umbilical cord-derived MSCs (UC-MSCs) offer biological advantages over other MSC sources (easily available, high proliferative capacity, and better repair efficacy). Pioneering work in our lab showed that MSCs prevent injury to the developing lung in a rat model mimicking BPD. However, there are still considerable challenges that must be overcome before MSCs can be effectively implemented in clinical trials. As such, UC-MSC heterogeneity is poorly understood, with concerns regarding variations from donors and batches. Thus, to improve the reproducibility of basic research and clinical applications, and to identify the optimal therapeutic cell product, better molecular characterization of UC-MSCs and the development of standardized BPD models will be essential in the clinical translation of MSC therapy for BPD. Moreover, considering that BPD is a disease of prematurity, the therapeutic potential of UC-MSCs isolated from preterm birth is of major interest. In the study presented here, using single-cell RNA sequencing (scRNA-seq), we characterized MSCs isolated from the UC of term and preterm pregnancies at delivery (term and preterm donors), as well as non-progenitor control cell line, human neonatal dermal fibroblasts (HNDFs). Moreover, we associated UC-MSC transcriptomic profiles with their therapeutic potential in hyperoxia-induced lung injury in neonatal rats. Finally, we developed and characterized a novel two-hit (2HIT) BPD model in neonatal mice, assessed UC-MSCs' optimal route of injection, timing, and dose, and evaluated their therapeutic effects in that model. We showed that UC-MSCs isolated from the majority of term and preterm donors, including preterm donors with pregnancy-related complications, have limited heterogeneity and possessed a transcriptome enriched in genes related to cell cycle and cell proliferation activity (termed "progenitor-like" cells). In contrast, UC-MSCs isolated from one term and two preterm donors with preeclampsia displayed a unique transcriptome comprised of many genes related to fibroblast activity, including extracellular matrix (ECM) organization (termed "fibroblast-like" cells). In addition, treatment with progenitor-like UC-MSCs, but not with fibroblast-like cells nor HNDFs, significantly improved lung structure, function, and pulmonary hypertension (PH) in hyperoxia-induced lung injury in neonatal rats. We identified marker genes for the therapeutic UC-MSCs (progenitor-like cells) and non-therapeutic cells (fibroblast-like cells and HNDFs). Among them, the high expression of major histocompatibility complex class I (MHCI) is associated with a reduced therapeutic effect. Furthermore, we developed a novel 2HIT BPD mice model with in-depth characterization of the innate immune response and lung injury. 2HIT injury caused a transient type 1 proinflammatory cytokine response and a significant decrease in type 2 anti-inflammatory cytokine lung expression and number of anti-inflammatory M2 type alveolar macrophages. Moreover, 2HIT mice showed impaired lung compliance and growth. Repeated intravenous (i.v.) injections of UC-MSCs at a dose of 20×10⁶ cells/kg body weight (BW) on postnatal day (PD) one and two improved survival, BW, lung compliance, and growth of 2HIT animals. In conclusion, scRNA-seq experimentation provided evidence that UC-MSCs isolated from different donors harbor different transcriptomes with progenitor-like or fibroblast-like characteristics. Only progenitor-like cells provided a therapeutic effect in hyperoxia-induced lung injury in neonatal rats. The development of a novel murine 2HIT BPD model allowed us to characterize the innate immune response and lung pathology and confirm the optimal dose of UCMSCs to provide therapeutic potential in that model. These results will enable better therapeutic selection of UC-MSCs and help improve treatment regimen prior to ultimate clinical translation.

<p>Uvod: Bronhopulmonalna displazija (BPD) je najče&scaron;ća i najteža respiratorna posledica prematuriteta. Utvrđivanje najznačajnijih faktora rizika za nastanak BPD kod novorođenčadi porođajne mase (PM) ispod 1500g može omogućiti procenu rizika za&nbsp; nastanak bolesti i identifikaciju novorođenčadi u visokom riziku, &scaron;to je važno za pružanje informacija roditeljima o prognozi,&nbsp; planiranje preventivnih i terapijskih mera i stratifikovanje novorođenčadi koja su u riziku za sprovođenje budućih istraživanja. Cilj: Utvrđivanje incidencije, stepena težine BPD, smrtnosti, identifikacija najznačajnijih prenatalnih i postnatalnih faktora rizika za nastanak BPD, konstrukcije modela predikcije za nastanak BPD. Materijal i metode: Istraživanje je sprovedeno na 504&nbsp; prevremeno rođene novorođenčadi PM&lt;1500g koja su rođena u porodili&scaron;tima u AP Vojvodini i lečena u tercijarnom Centru za neonatologiju i intenzivnu negu i terapiju, na Institutu za zdravstvenu za&scaron;titu dece i omladine Vojvodine u periodu od&nbsp; 2006.-2011. godine. Retrospektivno je analizirano prisustvo BPD, prema stepenima težine, smrtnost. Podaci su izdvojeni iz&nbsp; istorija bolesti za svako novorođenče, 30 potencijalnih prenatalnih i postnatalnih faktora je opisano deskriptivnom i univarijantnom statistikom. Statstički najznačajniji faktori su uneti u multifaktorsku logističku regresionu analizu u cilju&nbsp; konstrukcije prediktivnih modela za nastanak BPD u 1.,14. i 21. danu neonatalnog života. Podaci su obrađeni u StatSoft-ovom&nbsp; programskom paketu Statistica 10.0.&nbsp; Validacija modela predikcije je sprovedena u prospektivnom delu istraživanja, na 100&nbsp;&nbsp;&nbsp; prevremeno rođene novorođenčadi&lt;1500g, u periodu od 2012-2013. godine. Rezultati: U retrospektivnom delu&nbsp; istraživanja,&nbsp; od 504&nbsp; novorođenčeta PM&lt;1500 grama, umrlo je 17.65%, BPD je imalo 45.43% (blagu BPD 19.44%, srednje te&scaron;ku 19.84%,&nbsp; te&scaron;ku&nbsp; 6.15%), srednje te&scaron;ku i&nbsp; te&scaron;ku 25.99%.Antenatalna primena kortikosteroida je zastupljena u 47.02%, surfaktant&nbsp;&nbsp; je&nbsp;&nbsp; primenjen kod 69.78% novorođenčadi. Najznačajniji prenatalni prediktivni faktor rizika za nastanak BPD/smrtnog ishoda je horioamnionitis (OR 5.72; 95% CI 3.42-9.62), dok su protektivni faktori: prenatalna primene kortikosteroida (OR&nbsp; 0.41;&nbsp; 95%CI&nbsp; 0.29-0.60), porođaj carskim rezom (OR&nbsp; 0.24; 95% CI 0.16-0.36). Najznačajniji&nbsp; postnatalni prediktivni faktori rizika su: GS&nbsp; (p&asymp;0.00), PM (p&asymp;0.00), reanimacija u porođajnoj sali (OR 7.01; 95% CI 4.12-12.01), rana&nbsp; neonatalna&nbsp; sepsa&nbsp; (OR&nbsp; 7.35;&nbsp; 95%CI&nbsp; 3.79-14.58), RDS&nbsp; (p&asymp;0.00), primena surfaktanta (OR13,3;95%CI 8,2 - 21,67), DAP (OR 4.12; 95%CI&nbsp; 2.47-6.89),&nbsp; dok&nbsp; je&nbsp; ženski&nbsp; pol&nbsp; protektivan (OR&nbsp; 0.61; 95% CI 0.42-0.89). FiO2 i IPPV su u svim posmatranim danima značajni faktori rizika. Primena IPPV u 1. danu (OR 10.71;&nbsp; 95% CI 6.67-17.26); u ostalim danima rizik od BPD raste prema rastućoj invazivnosti respiratorne&nbsp; potpore.&nbsp; Konstruisani su modeli&nbsp; predikcije za 1, 14 i 21. dan života, modeli imaju visoku prediktivnu vrednost: ukupan procenat uspe&scaron;nosti&nbsp; modela je 84.26%-90.80%, modeli sa ne&scaron;to većim uspehom predviđaju&nbsp;&nbsp; prisustvo (85.36%-94.12%), nego odusustvo BPD (81.72-86.56%). OR modela je 28.07-103.04. Modeli su uspe&scaron;no validirani&nbsp; na 102 pacijenta sa ukupnim procentom uspe&scaron;nosti (82-90%), PPV (0.86-0.94) i NPV (0.76-0.87). Zaključak:&nbsp; Kori&scaron;ćenjem&nbsp; prenatalnih i postnatalnih kliničkih podataka moguće je predvideti nastanak BPD ili smrtnog ishoda.</p> / <p>Introduction: Bronchopulmonary dysplasia (BPD) is the most common serious pulmonary morbidity in very low birth weight (VLBW) infants. It is of clinical importance to determine clinical variables that are associated with BPD in order to identify infants who are at risk of developing BPD; it contributes to BPD prevention, may enable prognostic information for parents and future studies design. Objective: The aim of this study was to determine the incidence and severity of BPD, mortality rate in VLBW infants, to identify prenatal and postnatal predictive risk factors for bronchopulmonary dysplasia and competing outcome of death and to develop predictive models. Materials and Methods: Study was conducted in 504 VLBW infants born in the maternity hospitals in Vojvodina and admitted to tertiary Center for newborn and neonatal intensive care at the Institute for Child and Youth Health Care of Vojvodina, from January 2006. to December 2011. Data were retrospectively collected from clinical records for outcomes BPD or death; prenatal and postnatal factors associated with BPD were collected at three postnatal ages and examined by descriptive and univariate statistics; factors that were significantly associated with BPD and/or death were entered into a multivariate logistic regression analysis for develop predictive models. Data were analyzed using StatSoft&#39;s software package Statistica 10.0. Validation of the models were conducted in a prospective study in 102 VLBW infants born from January 2012. to December 2013. Results: There were 504 very low birth weight infants who were eligible for this study, 17.65% died, 45.43% developed BPD (mild BPD 19.44%, moderate 19.84%, severe 6.15%), moderate and severe 25.99%. The mean birth weight for the cohort was 1125.6&plusmn;280.9g, the mean gestation age was GS 28,78&plusmn;3,01, 49.21% were male. Surfactant received 69.78%, antenatal steroids 47.02% newborns. Key risk factors for BPD and/or death were: chorioamnionitis and maternal infections at delivery (OR 5.72; 95% CI 3.42-9.62); protective prenatal factors were: antenatal corticosteroid therapy (OR 0.41; 95%CI 0.29-0.60), cesarean delivery (OR 0.24; 95% CI 0.16-0.36). Postnatal rick factors were: GS (p&asymp;0.00), birth weight (p&asymp;0.00), delivery room resuscitation (OR 7.01; 95% CI 4.12-12.01), early neonatal sepsis (OR 7.35; 95%CI 3.79-14.58), RDS (p&asymp;0.00), surfactant (OR13,3;95%CI 8,2 - 21,67), DAP (OR4.12; 95% CI 2.47-6.89), while female gender was protective (OR 0.61; 95% CI 0.42-0.89). At each time point studied, FiO2 was significantly higher in BPD/death, as well as respiratory support; on the first day invasive respiratory support was significantly associated with BPD/death (IPPV and HFOV) (OR 10.71; 95% CI 6.67-17.26), in other days BPD was associated with increasing invasiveness of respiratory support. In multifactorial logistic regression analysis separately predictive models were developed at three postnatal ages, at 1st, 14th and 21st day. Models had high predictive performance: total success of the models were 84.26% - 90.80%, models successfully predicted the presence of BPD in 85.36% -94.12%, absence of the BPD in 81.72 - 86.56% cases. OR of models were 28.07-103.04. The models were successfully validated on 102 patients with a total percentage of success 82 - 90%, with PPV 0.86-0.94 and NPV 0.76-0.87. Conclusion: Using prenatal and postnatal clinical data it is possible to predict the development of BPD and/or death in very low birth weight infants. It is very important to identify risk factors for BPD development in order to decrease the incidence of BPD and mortality rate.</p>

Introduction: Le supplément d’oxygène et la nutrition parentérale (NP) sont les deux sources majeures de stress oxydant chez le nouveau-né. Lors de la détoxification des oxydants, le potentiel redox du glutathion s’oxyde. Notre hypothèse est que le supplément d’oxygène et la durée de la NP sont associés à un potentiel redox plus oxydé et à une augmentation de la sévérité de la dysplasie bronchopulmonaire (DBP). Patients et Méthodes: Une étude observationnelle prospective incluant des enfants de moins de 29 semaines d’âge gestationnel. Les concentrations sanguines de GSH et GSSG à jour 6-7 et à 36 semaines d’âge corrigé étaient mesurées par électrophorèse capillaire et le potentiel redox était calculé selon l’équation de Nernst. La sévérité de la DBP correspondait à la définition du NICHD. Résultats: Une FiO2≥ 25% au 7ième jour de vie ainsi que plus de 14 jours de NP sont significativement associés à un potentiel redox plus oxydé et à une DBP plus sévère. Ces relations sont indépendantes de l’âge de gestation et de la gravité de la maladie initiale. La corrélation entre le potentiel redox et la sévérité de la DBP n’est pas significative. La durée de la NP était responsable de 15% de la variation du potentiel redox ainsi que de 42% de la variation de la sévérité de la DPB. Conclusion: Ces résultats suggèrent que l’oxygène et la NP induisent un stress oxydant et que les stratégies visant une utilisation plus judicieuse de l’oxygène et de la NP devraient diminuer la sévérité de la DBP. / Introduction: oxygen supplementation and total parenteral solution (TPN) are two main clinical practices that sustain oxidative stress. Glutathione is a key molecule that detoxifies peroxides resulting in a more oxidized redox potential. We hypothesize that O2 supplementation and longer TPN duration are associated with both more oxidized redox potential and more severe bronchopulmonary dysplasia (BPD). Patients and methods: A prospective observational study including infants of less than 29 weeks gestational age. GSH and GSSG from whole blood sampled on day 6-7 and at 36 weeks of corrected age (CA) were measured by capillary electrophoresis and redox potential was calculated using Nernst equation. BPD was classified according to NICHD guidelines. Results: There was a significant association between FiO2 ≥ 25% on day 7 of life and TPN duration longer than 14 days and both more oxidized redox potential and more severe BPD. TPN duration explained both 15 % of total variation observed in redox potential and 42 % of total variation in BPD severity. These associations remained significant after adjustment for gestational age and illness severity. The relation between the severity of BPD and the redox potential in blood was not significant. The statistic power (1-β) to show an effect of redox potential on severity of BPD was 52%. Conclusion: Both redox potential of glutathione and BPD severity are both associated with early O2 supplement and TPN. Strategies targeting judicious use of O2 supplement and either decreasing the duration or using safer formulation of TPN are expected to help reducing BPD.

INTRODUÇÃO: Picos de pressão inspiratória excessivos e elevados volumes correntes (VT) durante a ventilação manual podem iniciar a resposta inflamatória no pulmão do prematuro. A manobra de insuflação pulmonar sustentada (IPS) tem sido estudada como um procedimento para melhorar a aeração pulmonar imediatamente após o nascimento. OBJETIVO: Avaliar a influência do ventilador manual em T (peça T) e do balão autoinflável (BAI) nas variáveis de mecânica respiratória durante a ventilação manual e a manobra de IPS, além da influência do treinamento como instrutor do Programa de Reanimação Neonatal da Sociedade Brasileira de Pediatria (PRN-SBP), na qualidade da ventilação. MÉTODOS: Em um estudo experimental, prospectivo e randomizado, 114 indivíduos, entre instrutores e não instrutores do PRN-SBP, ventilaram um manequim neonatal intubado, equivalente a um recém-nascido de 2500 gramas, por períodos de três minutos, utilizando um BAI e a peça T. A escolha do primeiro equipamento foi feita por randomização e os operadores não tinham acesso aos dados de mecânica respiratória durante a gravação. Ao final da ventilação manual, foi solicitado que cada indivíduo realizasse uma manobra de IPS durante 10 segundos, a uma pressão de 20 cmH2O. Para cada parâmetro de mecânica respiratória obtido durante a ventilação manual e a IPS, foi realizada uma comparação direta entre os equipamentos, considerando a formação e o treinamento dos participantes. Os dados foram obtidos por um sistema informatizado que permitiu a análise posterior. RESULTADOS: Em relação à ventilação manual, foi encontrada uma diferença nos valores do VT e do TI entre os equipamentos. Com o uso do BAI o VT foi de 28,5 (12,6) mL, mediana (amplitude interquartil) no grupo instrutores e 31,6 (14,0) mL no grupo não instrutores, enquanto que com a peça T foi de 20,1 (8,4) mL e 22,3 (8,8) mL, respectivamente. O TI encontrado com o uso do BAI foi de 0,5 (0,2) segundos, mediana (amplitude interquartil), tanto para instrutores como para não instrutores, enquanto que com a peça T foi de 1,0 (0,6) segundos e 1,1 (0,9) segundos, respectivamente. Em ambos os parâmetros não foram observadas diferenças entre os grupos de profissionais. A capacidade do operador de manter uma pressão alvo de 20 cmH2O durante os 10 segundos de IPS foi avaliada através da área sob a curva de pressão (ASC), que foi 1,7 vezes maior com o uso da peça T em relação ao BAI (p < 0,05). A pressão inspiratória máxima aplicada para a realização da IPS foi maior com o uso do BAI, enquanto que a pressão média das vias aéreas, avaliada entre o início e o final dos 10 segundos de procedimento, foi maior com o uso da peça T. Novamente não foram observadas diferenças entre os grupos de profissionais. CONCLUSÃO: A peça T resultou em menores valores de VT e maiores valores de TI independente do treinamento como instrutor do PRNSBP. A peça T permitiu uma maior eficácia na realização da manobra de IPS, representada pela manutenção da pressão alvo pelo período desejado e por uma maior pressão média nas vias aéreas em relação ao BAI / INTRODUCTION: During manual resuscitation of neonates, excessive peak inspiratory pressure (PI) and high tidal volume (VT) may trigger an inflammatory response in the lungs. The sustained lung inflation (SLI) maneuver has been studied as a procedure to improve pulmonary aeration immediately after birth. OBJECTIVE: To assess the influence of a T-piece manual resuscitator versus a self-inflating bag (SIB) on respiratory mechanics during manual ventilation and the SLI maneuver and the influence of training as a Brazilian Society of Pediatrics Neonatal Resuscitation Program instructor on the quality of ventilation. METHODS: In this experimental, prospective, randomized trial, 114 operators, including Brazilian Society of Pediatrics Neonatal Resuscitation Program instructors and non-instructors, ventilated an intubated neonatal resuscitation trainer (equivalent to a 2500g neonate) for 3-minute periods using an SIB or a Tpiece device. The choice of first device was random, and operators had no access to respiratory mechanics data during recording. At the end of the manual ventilation period, each operator was asked to perform an SLI maneuver for 10 seconds at 20 cmH2O. For each respiratory mechanics parameter obtained during manual ventilation and SLI, a direct comparison between devices was performed, taking operator training into account. Data were obtained through a computerized system for later analysis. RESULTS: During manual ventilation, differences in VT and TI were found between the two devices. The SIB was associated with a median (interquartile range) VT of 28.5 (12.6) mL in the instructor group and 31.6 (14.0) mL in the noninstructor group, whereas the T-piece was associated with a VT of 20.1 (8.4) mL in the instructor group and 22.3 (8.8) mL in the non-instructor group. Regarding TI, the SIB was associated with a median (interquartile range) value of 0.5 (0.2) seconds in instructors and non-instructors alike, whereas the T-piece was associated with a value of 1.0 (0.6) seconds in the instructor group and 1.1 (0.9) seconds in the non-instructor group. No differences between the operator groups were found in either parameter. Operator ability to maintain a 20-cmH2O pressure during the 10-second SLI maneuver was assessed by the area under the pressure curve (AUC), which was 1.7 times greater with the T-piece device than with the SIB (p < 0.05). Peak PI during the SLI maneuver was higher with the SIB, whereas mean airway pressure, assessed between start and end of the 10-second maneuver, was higher with the T-piece. Again, there were no differences between the operator groups. CONCLUSION: The T-piece was associated with lower VT and higher TI values regardless of training as a Brazilian Society of Pediatrics Neonatal Resuscitation Program instructor. The T-piece provided greater efficacy in performing the SLI maneuver, as represented by maintenance of target pressure throughout the desired period and by a higher mean airway pressure as compared with SIB use