Preterm Piglets Research Articles

Abdominal near-infrared spectroscopy measurements are lower in preterm infants at risk for necrotizing enterocolitis.

Near-infrared spectroscopy is a noninvasive method of measuring local tissue oxygenation (StO2). Abdominal StO2 measurements in preterm piglets are directly correlated with changes in intestinal blood flow and markedly reduced by necrotizing enterocolitis. The objectives of this study were to use near-infrared spectroscopy to establish normal values for abdominal StO2 in preterm infants and test whether these values are reduced in infants who develop necrotizing enterocolitis. We conducted a 2-year prospective cohort study where we prospectively measured abdominal StO2 in preterm infants, to establish reference values for preterm infants, and compared the near-infrared spectroscopy values with preterm infants in the cohort that developed necrotizing enterocolitis. Two neonatal ICUs: one at Texas Children's Hospital and the other at Ben Taub General Hospital in Houston, TX. We enrolled 100 preterm infants (< 32 weeks' gestation and < 1,500 g birth weight) between January 2007 and November 2008. None. Eight neonates with incomplete data were excluded. Mean abdominal StO2 in normal preterm infants (n = 78) during the first week of life was significantly higher than in those who later developed necrotizing enterocolitis (n = 14) (77.3% ± 14.4% vs 70.7% ± 19.1%, respectively, p = 0.002). An StO2 less than or equal to 56% identified preterm infants progressing to necrotizing enterocolitis with 86% sensitivity, 64% specificity, 96% negative predictive value, and 30% positive predictive value. Using logistic regression, StO2 less than or equal to 56% was independently associated with a significantly increased risk of necrotizing enterocolitis (odds ratio, 14.1; p = 0.01). Furthermore, infants with necrotizing enterocolitis demonstrated significantly more variation in StO2 both during and after feeding in the first 2 weeks of life. This study establishes normal values for abdominal StO2 in preterm infants and demonstrates decreased values and increased variability in those with necrotizing enterocolitis. Abdominal near-infrared spectroscopy monitoring of preterm infants may be a useful tool for early diagnosis and guiding treatment of necrotizing enterocolitis.

PO-0512 Microvascular Circulatory Dysregulation: A New Paradigm For Cardiovascular Compromise In The Preterm Newborn

Background and aims Cardiovascular compromise is associated with poor outcome in the preterm neonate, with gestational age and male sex as independent risk factors for hypotension, developmental injury and death. Recent work has highlighted the microvasculature as important in the development of cardiovascular compromise in the preterm. We aimed to further characterise microvascular changes that occur in the preterm newborn, identify potential windows for therapeutic intervention and explore the mechanisms underlying this dysfunction. Methods Preterm neonates were studied during circulatory transition. Microvascular blood flow was characterised over time by laser Doppler. We developed a guinea pig model for studying the mechanisms underlying regulation of blood flow (delivery at GA62/71) and also undertook studies in the preterm piglet. Results We observed significantly different patterns of microvascular tone regulation between male and female human (p = 0.01) and guinea pig (p = 0.01) neonates. Overproduction of vasodilators (carbon monoxide r = 0.495; p Conclusions We propose a paradigm shift whereby inherent physiological differences between the preterm and term, and male and female, lead to inappropriate dilatation of the microvasculature, insufficient preload to the struggling myocardium and functional hypovolaemia, thus resulting in central hypotension and cardiovascular compromise. We now have evidence of many of the mechanisms underlying this dysregulation and propose future research be directed at interventional opportunities.

PS-188 Intestino-trophic Effects Of Minimal Enteral Nutrition In Preterm And Term Piglets

Background and aims In preterm infants, slow advancement of minimal enteral nutrition (MEN), combined with parenteral nutrition (PN), may be important to increase food tolerance and minimise the risk of necrotizing enterocolitis (NEC). We hypothesised that MEN for five days would increase gut growth and gut hormone release relative to total parenteral nutrition (TPN). Methods Preterm and term piglets were delivered by caesarean section and fed TPN or PN+MEN (MEN: 0–64 mL bovine colostrum /kg/d) for five days. From day 5–26 all pigs were fed total enteral nutrition with milk-replacer. Pigs were euthanized at 0, 5 or 26 days of age, and gut weight, mucosal volume, L-cell density and plasma levels of GIP and GLP-2 were measured. Results Body weight gain was markedly reduced in preterm vs. term (P Conclusion Despite the compromised growth in preterm pigs, the intestine is highly growth-responsive to MEN just after birth in both preterm and term pigs. The effects of MEN on gut dimensions and gut peptide release are minimal after few weeks of full enteral nutrition. MEN provision may be important for short term gut maturation in preterm infants.

O-215 Necrotizing Enterocolitis Is Associated With Hippocampal Neuron Loss, Microglial Activation And Increased Il-8 Levels In Preterm Pigs

Background and aims Preterm birth predisposes to neurological sequelae. Necrotizing enterocolitis (NEC) may further increase the susceptibility to neurological damage, possibly via gut-derived inflammatory signals. To investigate this, we test if NEC severity and intestinal permeability in formula-fed preterm pigs is associated with histopathology, microglial activation, and increased proinflammatory cytokine levels in the hippocampus. Methods Forty-four preterm piglets were fed increasing doses of formula and euthanized on day five. Macroscopic NEC lesions were scored in five regions of the gut (stomach, proximal, middle, and distal small intestine, colon). Intestinal permeability was assessed by urinary lactulose-mannitol-ratio. Hippocampal IL-1β and IL-8 levels were determined by ELISA. Histopathology, neurodegeneration, and microglia were investigated by analyses of hematoxylin-eosin, Fluoro-jade B (FJB), and Iba-1 stained coronal sections, respectively. Results Proximal, middle, and distal small intestinal NEC score, and intestinal permeability correlated positively with IL-8 levels (all p Conclusions Acute development of NEC is associated with neuron loss, microglial activation, and increased IL-8 levels in the hippocampus of preterm pigs. Gut inflammatory disorders and increased intestinal permeability may affect the immature brain and contribute to long term neurological disorders.

PS-341a New Generation Lipid Emulsion Protects Against Lps-induced Brain Inflammation In Premature Piglets

<h3>Background</h3> Premature infants provided parenteral nutrition (PN) high in n-6 polyunsaturated fatty acids (PUFA) have increased risk of inflammatory disease, such as nosocomial sepsis. The pro-inflammatory insult can also contribute to injury and delayed neuronal growth in the perinatal brain. Provision of high long chain n-3 PUFA in parenteral lipids is associated with decreased inflammation and incidence of sepsis. The provision of n-3 PUFA, especially docosahexaenoic acid (DHA) also is critical for neurodevelopment in premature infants. <h3>Aim</h3> To determine whether a new generation lipid emulsion high in n-3 PUFA (SMOFlipid) protects against inflammation and improves neuroprotection in response to lipopolysaccharide (LPS) compared to a lipid emulsion high in n-6 PUFA (Intralipid). <h3>Methods</h3> Preterm piglets delivered 7 d preterm were assigned into two groups receiving complete TPN containing either Intralipid or SMOFlipid at 10 g*kg^-1*d^-1 for 10 d. On day 10, sub-groups of piglets were assigned to receive either an 8-hr infusion of lipopolysaccharide (2 mg/kg) or control saline and target gene expression in brain tissue was analysed. <h3>Results</h3> LPS increased brain gene expression of pro-inflammatory cytokines IL-6, IL-8, and TNF in the Intralipid group, but not the SMOFlipid group. The gene expression of the anti-inflammatory cytokine Il-10 was increased in both LPS-treated lipid groups. Brain-derived neuronal growth factor, a marker of neuronal proliferation, was deceased in the LPS-treated SMOFlipid group, but not the LPS-treated Intralipid group. <h3>Conclusions</h3> SMOFlipid protected against LPS-induced inflammation, but did not acutely increase the expression of the neuroprotective protein, BDNF, in the presence of LPS.

173: Probiotics in a gnotobiotic piglet model of preterm infants

Mucosal surfaces of newborns are colonized by microbes in dependence on their delivery and nutrition. Are probiotics safety to Caesarean section derived immunocompromised preterm infants? Hysterectomy derived preterm germ-free piglets, either treated or non-treated with serum, were colonized with Lactobacillus rhamnosus (LGG) four hours after hysterectomy. Bacterial translocation of LGG, its protection against subsequent infection of the piglets with Salmonella Typhimurium, and induction of plasma and intestinal levels of inflammatory cytokines IL-1 beta, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha (xMAP), and HMGB1 (ELISA) were estimated. LGG did not translocate in one week old preterm piglets. It was found in mesenteric lymph nodes in piglets subsequently infected with S. Typhimurium only but it did not translocate to other organs (blood, liver, spleen, and lungs). Inflammatory cytokine values were not induced by LGG alone but they were dramatically increased in piglets infected with Salmonella . The piglets treated with mixed serum of adult sows showed reduced levels of inflammatory cytokines as in the intestine so in plasma. It is necessary to develop highly sensitive animal models to evaluate a safety of different probiotics for immunocompromised preterm infants. A high attention should be paid to a selection of suitable markers to evaluate possible risk of these probiotics. Inflammatory cytokines in the intestine/feces of preterm newborns should be a suitable candidates of such markers. This work was supported by Grants 13-14736S of the Czech Science Foundation , FR-TI4/504 of the Ministry of Industry and Trade of the Czech Republic and the Institutional Research Concept RVO: 61388971 of the Institute of Microbiology .

Lactobacillus rhamnosus HN001 decreases the severity of necrotizing enterocolitis in neonatal mice and preterm piglets: evidence in mice for a role of TLR9.

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and develops partly from an exaggerated intestinal epithelial immune response to indigenous microbes. There has been interest in administering probiotic bacteria to reduce NEC severity, yet concerns exist regarding infection risk. Mechanisms of probiotic activity in NEC are unknown although activation of the microbial DNA receptor Toll-like receptor-9 (TLR9) has been postulated. We now hypothesize that the Gram-positive bacterium Lactobacillus rhamnosus HN001 can attenuate NEC in small and large animal models, that its microbial DNA is sufficient for its protective effects, and that protection requires activation of the Toll-like receptor 9 (TLR9). We now show that oral administration of live or UV-inactivated Lactobacillus rhamnosus HN001 attenuates NEC severity in newborn mice and premature piglets, as manifest by reduced histology score, attenuation of mucosal cytokine response, and improved gross morphology. TLR9 was required for Lactobacillus rhamnosus-mediated protection against NEC in mice, as the selective decrease of TLR9 from the intestinal epithelium reversed its protective effects. Strikingly, DNA of Lactobacillus rhamnosus HN001 reduced the extent of proinflammatory signaling in cultured enterocytes and in samples of resected human ileum ex vivo, suggesting the therapeutic potential of this probiotic in clinical NEC. Taken together, these findings illustrate that Lactobacillus rhamnosus HN001 is an effective probiotic for NEC via activation of the innate immune receptor TLR9 and that Lactobacillus rhamnosus DNA is sufficient for its protective effects, potentially reducing concerns regarding the infectious risk of this novel therapeutic approach.

Prematurity Reduces Functional Adaptation to Intestinal Resection in Piglets

Necrotizing enterocolitis and congenital gastrointestinal malformations in infants often require intestinal resection, with a subsequent risk of short bowel syndrome (SBS). We hypothesized that immediate intestinal adaptation following resection of the distal intestine with placement of a jejunostomy differs between preterm and term neonates. Preterm or term piglets were born by cesarean section and fed enterally for 2 days. On day 2, piglets were subjected to 50% distal intestinal resection with placement of a jejunostomy. On the following 4-5 days, piglets received parenteral nutrition with gradually increasing doses of enteral nutrition (bovine colostrum). Intestinal tissue samples were collected at delivery and 2 and 6-7 days after birth for histological examination and assessment of digestive enzyme activities. Preterm and term piglets showed similar increases in intestinal weight and digestive enzyme activities from birth to 2 days. On days 6-7 after birth, the remnant intestine showed a similar density (g/cm) and mucosal mass in term and preterm piglets, but villus height, crypt depth, enzyme activities (sucrase, maltase, dipeptidyl peptidase IV [DPPIV]), and hexose uptake capacity were significantly higher in term piglets (P < .05). Preterm piglets were more prone to develop hypoglycemia, respiratory distress syndrome, dehydration, and circulatory instability after surgery compared with term piglets. Studies on intestinal adaptation after resection are feasible in both preterm and term piglets, but intensive clinical support is required when rearing preterm piglets with SBS. Physiological instability and immaturity of the intestine may explain the fact that immediate adaptation after resection is reduced in preterm vs term neonates.

Effects of Glucocorticoid Exposure on Growth and Structural Maturation of the Heart of the Preterm Piglet

Inadequate maintenance of systemic blood flow in neonates following preterm birth is associated with increased morbidity and mortality, and may be due in part to structural immaturity of the myocardium. Maternal glucocorticoid administration is associated with improved cardiovascular function, and possibly promotes structural maturation of the myocardium. This study assessed the structural maturity of the myocardium in male and female preterm and term piglets, and preterm piglets exposed to a regimen of maternal glucocorticoids as used clinically. In preterm, term and glucocorticoid exposed preterm piglets cardiomyocyte maturity was examined by measuring the proportion of binucleated myocytes and the volumes of single living ventricular cardiomyocytes with fluorescence microscopy. Ventricular apoptosis and proliferation were measured by immunohistochemistry. Preterm piglet hearts had fewer binucleated myocytes, smaller myocytes, and more proliferative and fewer apoptotic nuclei than term hearts. Maternal glucocorticoid treatment resulted in increased binucleation with no increase in myocyte volume, and levels of proliferation and apoptosis that were more similar to the term heart. Atrial weights were increased and in female piglets there was an increase in the ratio of left to right ventricular weight. The observed changes in atrial mass and myocyte structural maturation correlated with changes in cardiac function of isolated hearts of littermates. In conclusion, the association between increased myocardial maturation following glucocorticoid exposure, improved cardiac function in littermates, and clinical improvement in human neonatal cardiac function exposed to antenatal glucocorticoids, suggests that glucocorticoid exposure contributes to improved cardiovascular function in preterm infants by promoting myocardial structural maturity.

Expression of Adrenoceptor Subtypes in Preterm Piglet Heart Is Different to Term Heart

Preterm delivery increases the risk of inadequate systemic blood flow and hypotension, and many preterm infants fail to respond to conventional inotrope treatments. If the profile of cardiac adrenoceptor subtypes in the preterm neonate is different to that at term this may contribute to these clinical problems. This study measured mRNA expression of β1, β2, α1A, α2A and α2B-adrenoceptor subtypes by real time PCR in term (113d), preterm (91d) and preterm piglets (91d) exposed to maternal glucocorticoid treatment. Abundance of β-adrenoceptor binding sites in the left ventricle was measured using saturation binding assays. Relative abundance of β1-adrenoceptor mRNA in untreated preterm hearts was ∼50% of term abundance in both left and right ventricles (P<0.001). Trends in receptor binding site density measurements supported this observation (P = 0.07). Glucocorticoid exposure increased β1-adrenoceptor mRNA levels in the right ventricle of preterm hearts (P = 0.008) but did not alter expression in the left ventricle (P>0.1). Relative abundance of α1A-adrenoceptor mRNA was the same in preterm and term piglet hearts (P = >0.1) but was reduced by maternal glucocorticoid treatment (P<0.01); α2A-adrenoceptor mRNA abundance was higher in untreated and glucocorticoid exposed preterm piglet hearts than in term piglets (P<0.001). There was no difference between male and female piglets in mRNA abundance of any of the genes studied. In conclusion, there is reduced mRNA abundance of β1-adrenoceptors in the preterm pig heart. If this lower expression of β-adrenoceptors occurs in human preterm infants, it could explain their poor cardiovascular function and their frequent failure to respond to commonly used inotropes.

Parenteral lipids and partial enteral nutrition affect hepatic lipid composition but have limited short term effects on formula-induced necrotizing enterocolitis in preterm piglets

Rapid transition from total parenteral nutrition (TPN) to enteral feeding is a risk factor for necrotizing enterocolitis (NEC) in preterm infants. We hypothesized that partial enteral nutrition with colostrum, increased proportion of n-3 polyunsaturated fatty acids (PUFA), or exclusion of lipid in TPN would affect short term NEC sensitivity and liver function. Preterm piglets were fed for three days after birth: 1) TPN with a standard lipid emulsion (Nutriflex Lipid Plus, TPN control group, n = 19), 2) PN plus bovine colostrum as partial enteral nutrition (PN/COL, n = 18), 3) TPN with fish oil (FO) lipids (Omegaven, TPN/FO, n = 19), or 4) TPN with no lipid (TPN/NL, n = 22). After TPN, piglets were fed formula for two days before tissue collection. None of the treatments had consistent effect on NEC incidence (∼40-50% across all groups), intestinal morphology and function, relative to TPN. In the liver, there were no signs of steatosis but PN/COL decreased the n-6 PUFA levels, leading to higher n-3/n-6 ratio, GGT activity, and plasma cholesterol and albumin levels, relative to TPN (all p < 0.05). TPN/FO increased the hepatic n-3 levels and n-3/n-6 ratio. TPN/NL treatment led to decreased hepatic n-6 level, n-3/n-6 ratio and bilirubin, albumin and triglycerides, and lowered blood clotting strength (-30%, TPN/NL vs. TPN/COL, p < 0.05). Partial enteral nutrition with colostrum, increased n-3 PUFAs in TPN, or removal of lipid from the TPN, all affect hepatic lipids and proteins in preterm neonates. These effects do not translate into improved hepatic function or NEC resistance, at least not short term.

Dual purpose use of preterm piglets as a model of pediatric GI disease

Necrotizing enterocolitis (NEC) is the most common gastrointestinal complication in human neonates, yet the pathogenesis of this disease remains poorly understood. A fundamental approach to understanding the etiology and underlying biology of NEC is the use of in vivo experimental animal models, primarly neonatal rodents and pigs. The rodent models using rats and mice have provided a much of the experimental evidence showing the protective influence of breast milk and the role of specific molecular mechanisms involved in the premature innate immune and intestinal injury response. A key advantage of mice is the abilty to test how genetic disruption of specific genes alters the NEC phenotype. More recently, pigs have emerged as an animal model of NEC and used to establish the role of bacterial colonization, prematurity, parenteral nutrition and antibiotic therapy. This review will outline some of the advantages and disadvantages of both rodent and pig models and highlight the lessons learned about NEC pathobiology from these different experimental models.

Raw bovine milk improves gut responses to feeding relative to infant formula in preterm piglets

For preterm neonates, the quality of the first milk is crucial for intestinal maturation and resistance to necrotizing enterocolitis (NEC). Among other factors, milk quality is determined by the stage of lactation and processing. We hypothesized that unprocessed mature bovine milk (BM; raw bovine milk) would have less bioactivity than corresponding bovine colostrum (BC) in a preterm pig model, but have improved bioactivity relative to its homogenized, pasteurized, spray-dried equivalent, whole milk powder (WMP), or a bovine milk protein-based infant formula (IF). For 5 days, newborn preterm pigs received parenteral and enteral nutrition consisting of IF (n = 13), BM (n = 13), or BC (n = 14). In a second study, WMP (n = 15) was compared with IF (n = 10) and BM (n = 9). Compared with pigs fed IF, pigs that were fed BM had significantly improved intestinal structure (mucosal weight, villus height) and function (increased nutrient absorption and enzyme activities, decreased gut permeability, nutrient fermentation, and NEC severity). BC further improved these effects relative to BM (lactase activity, lactose absorption, plasma citrulline, and tissue interleukin-8). WMP induced similar effects as BM, except for lactase activity and lactose absorption. In conclusion, the maturational and protective effects on the immature intestine decreased in the order BC>BM>WMP, but all three intact bovine milk diets were markedly better than IF. The stage of lactation (colostrum vs. mature milk) and milk processing (e.g., homogenization, fractionation, pasteurization, spray-drying) are important factors in determining milk quality during the early postnatal period of preterm neonates.

GLP‐2 Delays but Does Not Prevent the Onset of Necrotizing Enterocolitis in Preterm Pigs

Necrotizing enterocolitis (NEC) is complex disease thought to occur as a result of an immaturity of the gastrointestinal tract of preterm infants. Intestinal dysfunction induced by total parental nutrition (TPN) may increase the risk for NEC upon introduction of enteral feeding. We hypothesized that the intestinal trophic and anti-inflammatory actions previously ascribed to the gut hormone, glucagon-like peptide-2 (GLP-2), would reduce the incidence of NEC when given in combination with TPN in preterm piglets. Preterm, newborn piglets were nourished by TPN and infused continuously with either human GLP-2 (100 μg · kg⁻¹ · day⁻¹) or control saline for 2 days (n = 12/group). On day 3, TPN was discontinued and pigs were given orogastric formula feeding every 3 hours, and continued GLP-2 or control treatment until the onset of clinical signs of NEC for an additional 96 hours and tissue was collected for molecular and histological endpoints. GLP-2 treatment delayed the onset of NEC but was unable to prevent a high NEC incidence (~70%) and severity that occurred in both groups. GLP-2-treated pigs had less histological injury and increased proximal intestinal weight and mucosal villus height, but not crypt depth or Ki-67-positive cells. Inflammatory markers of intestinal myeloperoxidase were unchanged and serum amyloid A levels were higher in GLP-2-treated pigs. GLP-2 did not prevent NEC and a proinflammatory response despite some reduction in mucosal injury and increased trophic effect.

Similar efficacy of human banked milk and bovine colostrum to decrease incidence of necrotizing enterocolitis in preterm piglets

Preterm birth and formula feeding predispose to necrotizing enterocolitis (NEC) in infants. As mother's milk is often absent following preterm delivery, infant formula (IF) and human donor milk (HM) are frequently used as alternatives. We have previously shown that porcine and bovine colostrum (BC) provide similar NEC protection in preterm piglets relative to IF. We hypothesized that HM exerts similar effects and that this effect is partly species-independent. Preterm piglets (n = 40) received 2 days of total parenteral nutrition, followed by a rapid transition to full enteral feeding (15 ml·kg(-1)·2 h(-1)) for 2 days using BC (n = 13), HM (n = 13), or IF (n = 14). Intestinal passage time and hexose absorption were tested in vivo. Body and organ weights were recorded on day 5, and macroscopic NEC lesions in the gastrointestinal tract were assessed. Intestinal samples were collected for determination of histomorphology, histopathology, tissue IL-6 and IL-8, organic acids, bacterial adherence by fluorescence in situ hybridization score, and digestive enzyme activities. Relative to IF, pigs from BC and HM showed longer intestinal passage time; higher weight gain, hexose absorptive capacity, mucosal proportion, and enzyme activities; lower NEC incidence, organic acid concentration, and IL-8 concentration; and reduced histopathology lesions. Tissue IL-6 concentration and bacterial adherence score were lower for HM, relative to both BC and IF groups. We conclude that BC and HM are both superior to IF in stimulating gut structure, function, and NEC resistance in preterm piglets. BC may be a relevant alternative to HM when mother's milk is unavailable during the first week after preterm birth.

1131 Cardiovascular and Hormonal Responses to Hypoxic Stress in the Preterm Piglet

Background and AimsImmature control of the cardiovascular system may be a contributing factor to poor cardiovascular function and associated increases in mortality and morbidity in preterm infants. This study aimed...

1117 A Pig Model of the Preterm Neonate: Anthropometric and Physiological Characteristics

Background and AimsLarge animal models are an essential research tool to investigate the physiology of the preterm infant, which remains poorly understood. We aim to describe the pig model of...

Left ventricular output and aortic blood flow in response to changes in preload and afterload in the preterm piglet heart

Low systemic blood flow occurs in up to 30% of infants born at less than 30 wk gestation. It is associated with increased morbidity and mortality, and current treatments are ineffective in 40% of cases. The aim of this study was to assess the ability of the preterm heart to respond to the acute shifts in preload and afterload that occur at the time of birth. Myocardial and coronary vascular function was assessed using an isolated working heart model in term (115 days) and preterm (92 days) piglets. Cardiac output/kg body wt in preterm hearts was ∼50% lower than that of term hearts (P = 0.001). Pressure development was similar in term and preterm hearts. Elevations in preload increased cardiac output and aortic flow similarly in term and preterm hearts, demonstrating significant preload "reserve". By contrast, elevations in afterload markedly depressed aortic flow, with a greater proportion of cardiac output being distributed to coronary flow in preterm hearts at high afterloads. The demands of increased workload were associated with greater increases in coronary flow in preterm hearts compared with term hearts. In preterm hearts, exposure to maternal glucocorticoids resulted in increased aortic flow when afterload was below 25 mmHg. These data suggest the preterm heart lacks the functional capacity to acutely adapt to postnatal afterload. To maximize systemic blood flow in preterm infants, treatments limiting afterload, while harnessing significant preload reserve, should be further explored.

Guts, germs and glucose: understanding the effects of prematurity on the interaction between bacteria and nutrient absorption across the intestine

Guts, germs and glucose: understanding the effects of prematurity on the interaction between bacteria and nutrient absorption across the intestine

Treating Neonatal Seizures: is Gaba Still Exciting after Birth?

Background and Aims: Antiepileptic drugs (AEDs) do not effectively control seizures in newborn brain and there is growing concern that use of standard AEDs such as phenobarbital may exacerbate seizures and brain injury. Recent data suggests this may be due to the changing role of the GABAA receptor (an AED target) during normal neurodevelopment, a process tightly coupled to developmental expression of the chloride co-transporter proteins NKCC1 and KCC2. The timing of the 'switch' in GABAA receptor function from excitation to inhibition is unclear and in human may not be completed until 3-4 months of age. The aim of this project was to establish the developmental profile of NKCC1, KCC2 and the GABAA receptor µ1 and µ3 subunits in piglet brain. Methods: Preterm and term piglets of several different gestational ages around birth were obtained by caesarean section or spontaneous delivery. Brain tissue was collected from several brain regions and expression analysed by western blot. Results: In parietal cortex the switch between NKCC1 and KCC2 and, GABAA receptor µ1 and µ3 expression was evident by P3. The switch in GABAA receptor µ1 and µ3 expression had not yet occurred in the frontal, temporal or occipital cortex. NKCC1, KCC2 analysis is ongoing. Conclusions: Efficacy of AEDs in neonatal brain may depend on regional and temporal maturation of inhibition. Furthermore changes in GABAA receptor expression as we have demonstrated following HI and seizures will influence receptor pharmacology. There is a critical need to develop effective treatment strategies specific to the neonatal brain.