RESUMEN
Necrotizing enterocolitis (NEC) is a devastating bowel necrosis that predominantly affects preterm infants and is characterized by an imbalance toward a proinflammatory state. Fish oil or omega-3 long-chain polyunsaturated fatty acids have the potential to modulate inflammation. In this article, the authors examine the evidence in support of fish oil supplementation to alter the inflammatory response and potentially reduce the risk of NEC.
Asunto(s)
Ácidos Docosahexaenoicos/uso terapéutico , Ácido Eicosapentaenoico/uso terapéutico , Enterocolitis Necrotizante/prevención & control , Aceites de Pescado/uso terapéutico , Inflamación/inmunología , Suplementos Dietéticos , Enterocolitis Necrotizante/epidemiología , Enterocolitis Necrotizante/inmunología , Humanos , Incidencia , Recién Nacido , Recien Nacido Prematuro , Recién Nacido de muy Bajo PesoRESUMEN
Oropharyngeal administration of mother's own milk-placing drops of milk directly onto the neonate's oral mucosa-may serve to (ex utero) mimic the protective effects of amniotic fluid for the extremely low birth weight infant; providing protection against necrotizing enterocolitis. This article presents current evidence to support biological plausibility for the use of OroPharyngeal Therapy with Mother's Own Milk (OPT-MOM) as an immunomodulatory therapy; an adjunct to enteral feeds of mother's milk administered via a nasogastric or orogastric tube. Current methods and techniques are reviewed, published evidence to guide clinical practice will be presented, and controversies in practice will be addressed.
Asunto(s)
Calostro/inmunología , Citocinas/inmunología , Nutrición Enteral/métodos , Enterocolitis Necrotizante/prevención & control , Inmunomodulación , Tejido Linfoide/inmunología , Leche Humana/inmunología , Orofaringe/inmunología , Líquido Amniótico , Enterocolitis Necrotizante/inmunología , Femenino , Humanos , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recién Nacido , Recien Nacido Prematuro , Madres , EmbarazoRESUMEN
BACKGROUND: Extremely premature (birth weight < 1250 g) infants are at high risk for acquiring late-onset sepsis and necrotizing enterocolitis, which are associated with significant mortality and morbidity. Own mother's milk contains protective (immune and trophic) biofactors which provide antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory functions, enhance intestinal microbiota, and promote intestinal maturation. Many of these biofactors are most highly concentrated in the milk expressed by mothers of extremely premature infants. However, since extremely premature infants do not receive oral milk feeds until 32 weeks post-conceptional age, they lack the potential benefit provided by milk (biofactor) exposure to oropharyngeal immunocompetent cells, and this deficiency could contribute to late-onset sepsis and necrotizing enterocolitis. Therefore, oropharyngeal administration of own mother's milk may improve the health outcomes of these infants. OBJECTIVES: To compare the effects of oropharyngeal administration of mother's milk to a placebo, for important clinical outcomes, including (1A) reducing the incidence of late-onset sepsis (primary outcome) and (1B) necrotizing enterocolitis and death (secondary outcomes). To identify the biomechanisms responsible for the beneficial effects of oropharyngeal mother's milk for extremely premature infants, including; (2A) enhancement of gastrointestinal (fecal) microbiota (2B) improvement in antioxidant defense maturation or reduction of pro-oxidant status, and (2C) maturation of immunostimulatory effects as measured by changes in urinary lactoferrin. METHODS/DESIGN: A 5-year, multi-center, double-blind, randomized controlled trial designed to evaluate the safety and efficacy of oropharyngeal mother's milk to reduce the incidence of (1A) late-onset sepsis and (1B) necrotizing enterocolitis and death in a large cohort of extremely premature infants (n = 622; total patients enrolled). Enrolled infants are randomly assigned to one of 2 groups: Group A infants receive 0.2 mL of own mother's milk, via oropharyngeal administration, every 2 hours for 48 hours, then every 3 hours until 32 weeks corrected-gestational age. Group B infants receive a placebo (0.2 mL sterile water) following the same protocol. Milk, urine, oral mucosal swab, and stool samples are collected at various time points, before, during and after the treatment periods. Health outcome and safety data are collected throughout the infant's stay. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02116699 on 11 April 2014. Last updated: 26 May 2015.
Asunto(s)
Calostro , Nutrición Enteral/métodos , Recien Nacido Extremadamente Prematuro , Recién Nacido de muy Bajo Peso , Peso al Nacer , Protocolos Clínicos , Calostro/química , Calostro/inmunología , Método Doble Ciego , Nutrición Enteral/efectos adversos , Enterocolitis Necrotizante/etiología , Enterocolitis Necrotizante/mortalidad , Enterocolitis Necrotizante/prevención & control , Femenino , Edad Gestacional , Mortalidad Hospitalaria , Humanos , Lactante , Mortalidad Infantil , Fenómenos Fisiológicos Nutricionales del Lactante , Recién Nacido , Masculino , Estado Nutricional , Mortalidad Perinatal , Embarazo , Proyectos de Investigación , Factores de Riesgo , Sepsis/etiología , Sepsis/mortalidad , Sepsis/prevención & control , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
Although supplementation of preterm formula with polyunsaturated fatty acids (PUFA) has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in animal models and clinical trials, the mechanisms remain elusive. We hypothesized that the protective effect of PUFA on NEC may be due to the ability of PUFA to suppress Toll-like receptor (TLR) 4 and platelet-activating factor receptor (PAFR) gene expression (molecules that are important in the pathogenesis of NEC) in epithelial cells. To investigate the efficacy of different PUFA preparations on NEC in a neonatal rat model, we compared the incidence of NEC among the four PUFA supplemented groups--A: arachidonic acid and docosahexaenoic acid (AA+DHA), B: egg phospholipids (EP), C: DHA, and D: control without PUFA. PUFA supplementation reduced the incidence of NEC and inhibited intestinal PAFR and TLR4 gene expression compared with the controls. To validate the in vivo observations, IEC-6 cells were exposed to PAF after pretreatment with AA or DHA. Both AA and DHA supplementation blocked PAF-induced TLR4 and PAFR mRNA expression in these enterocytes. These results suggest that PUFA modulates gene expression of key factors involved in experimental NEC pathogenesis. These effects might in part explain the protective effect of PUFA on neonatal NEC.
Asunto(s)
Suplementos Dietéticos , Enterocolitis Necrotizante/metabolismo , Enterocolitis Necrotizante/prevención & control , Ácidos Grasos Insaturados/administración & dosificación , Ácidos Grasos Insaturados/metabolismo , Mediadores de Inflamación/metabolismo , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Enterocolitis Necrotizante/genética , Regulación de la Expresión Génica/efectos de los fármacos , Incidencia , Inflamación/genética , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
The histopathology of necrotizing enterocolitis (NEC) is characterized by destruction of the mucosal layer in initial stages and by transmural necrosis of the intestinal wall in advanced stages of the disease. To test the hypothesis that enhanced epithelial apoptosis is an initial event underlying the gross histologic changes, we analyzed epithelial apoptosis and tissue morphology in an animal model of NEC and evaluated the effect of caspase inhibition on the incidence of experimental NEC in this model. Apoptosis was analyzed with terminal deoxynucleotidyltransferase-mediated dUTP-FITC nick end labeling (TUNEL) staining in intestinal sections and by measuring caspase 3 activity from intestinal lysates of neonatal rats subjected to formula feeding and cold/asphyxia stress (FFCAS) and from mother-fed (MF) controls. Morphologic evaluation was based on hematoxylin and eosin staining of intestinal sections. FFCAS resulted in histologic changes consistent with NEC, which were absent from MF animals. FFCAS was also associated with a significantly increased rate of nuclear DNA fragmentation in the small intestinal epithelium compared with MF. Elevated tissue caspase 3 activity confirmed the presence of apoptosis in samples with increased DNA fragmentation. Analysis of the coincidence of morphologic damage and apoptosis in corresponding tissue sections indicated that apoptosis precedes gross morphologic changes in this model. Furthermore, supplementation of formula with 8 boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, significantly reduced the incidences of apoptosis and experimental NEC. These findings indicate that in neonatal rats FFCAS induces epithelial apoptosis that serves as an underlying cause for subsequent gross tissue necrosis.