Intestinal protein and LPH synthesis in parenterally fed piglets receiving partial enteral nutrition and enteral insulinlike growth factor 1

BACKGROUND: Providing partial enteral nutrition (PEN) supplemented with insulinlike growth factor-1 (IGF-1) to parenterally fed piglets increases lactase-phlorizin hydrolase (LPH) activity, but not LPH mRNA. The current aim was to investigate potential mechanisms by which IGF-1 up-regulates LPH activity. METHODS: Newborn piglets (n = 15) received 100% parenteral nutrition (TPN), 80% parenteral nutrition + 20% parenteral nutrition (PEN), or PEN + IGF-1 (1.0 mg. kg-1. d-1) for 7 days. On day 7, [2H3]-leucine was intravenously administered to measure mucosal protein and brush border LPH (BB LPH) synthesis. RESULTS: Weight gain, nutrient intake, and jejunal weight and length were similar among the treatment groups. Partial enteral nutrition alone increased mucosal weight, villus width and cross-sectional area, LPH activity, mRNA expression, and high mannose LPH precursor (proLPHh) abundance compared with TPN (P<0.05). Insulinlike growth factor-1 further increased mucosal weight, LPH activity, and LPH activity per unit BB LPH approximately twofold over PEN alone (P < 0.05) but did not affect LPH mRNA or the abundance of proLPHh (one of the LPH isoforms) or mature LPH. Isotopic enrichment of [2H3]-leucine in plasma, mucosal protein, and LPH precursors, and the fractional and absolute synthesis rates of mucosal protein and LPH were similar among the treatment groups. Insulinlike growth factor-1 treatment increased total mucosal protein synthesis (60%, P < 0.05) but not LPH synthesis compared with the other two groups. CONCLUSIONS: Because IGF-1 did not affect the fractional synthesis rate of either mucosal protein or LPH, the authors suggest that enteral IGF-1 increases mucosal protein mass and LPH activity by suppressing mucosal proteolytic degradation.     

Glucagon-like peptide 2 stimulates intestinal nutrient absorption in parenterally fed newborn pigs

OBJECTIVES: Parenteral nutrition is a critically important intervention for children with intestinal dysfunctions. However, total parenteral nutrition (TPN) with no enteral feeding is associated with small intestine atrophy and malabsorption, which complicate the transition to enteral nutrition. The objective of the present study was to evaluate the therapeutic potential of the intestinotrophic peptide glucagon-like peptide 2 (GLP-2), which reduces TPN-associated atrophy and maintains nutrient absorption in adult rats, for preventing nutrient malabsorption in neonates receiving TPN. METHODS: Term pigs obtained by cesarean delivery received from birth TPN alone (TPN; n = 7) or TPN with GLP-2 (25 nmol . kg(-1) . d(-1); GLP-2; n = 8) or were fed sow milk enterally (n = 7). The small intestine was removed on postnatal day 6 to measure morphological responses and absorption of glucose, leucine, lysine and proline by intact tissues and brush border membrane vesicles and to quantify the abundances of mRNA and protein for enterocyte glucose transporters (SGLT-1 and GLUT2). RESULTS: Relative to TPN alone, administration of GLP-2 resulted in small intestines that were larger (P < 0.01), had greater abundances of mRNA and protein for SGLT-1, but not for GLUT2, and had higher capacities to absorb nutrients (P < 0.01). Moreover, the intestines of GLP-2 pigs were comparable in size and absorptive capacities with those of pigs fed sow milk enterally. CONCLUSIONS: Providing GLP-2 to neonates receiving TPN prevents small intestine atrophy, results in small intestine absorptive capacities that are comparable to when nutrients are provided enterally and may accelerate the transition from TPN to enteral nutrition.     

GLP-2 levels in infants with intestinal dysfunction.

Glucagon Like Peptide 2 (GLP-2) has been proposed as an important regulatory hormone in nutrient absorption. The present study was conducted in human infants with intestinal dysfunction undergoing surgery, correlating postprandial GLP-2 levels with intestinal length, nutrient absorption, and patient outcome. We hypothesized that GLP-2 levels would be inversely related to nutrient absorption; we further hypothesized that post prandial GLP-2 levels would be predictive of the ability to wean patients from total parenteral nutrition (TPN), and tolerance of enteral feeding. Infants prospectively identified with nutrient malabsorption following intestinal surgery were monitored and after initiation of feeds GLP-2 levels were measured in the fed state. Intestinal length was recorded intraoperatively and nutrient absorption was quantified using both a balance study, and carbohydrate probe method. 12 infants had GLP-2 levels successfully measured; two patients had repeated studies. Average gestational age was 32.7 +/- 3.4 wk, age at testing was 1.7 +/- 1.4 mo and average weight was 3.5 +/- 1.1 kg. Causes of intestinal loss were necrotizing enterocolitis, atresia and volvulus. Five patients had severe short bowel syndrome (<50% of normal small intestinal length), 3 died. GLP-2 levels were best correlated with residual small intestinal length (r2 = 0.75). Correlations with total intestinal length including colon were less significant; residual colon appeared to not contribute to measurable GLP-2 production. GLP-2 levels were well correlated with tolerance of enteral feeds. Contradicting the initial hypothesis, GLP-2 levels were directly correlated with nutrient absorptive capacity (correlation with fat absorption: r2 = 0.72, carbohydrate = 0.50 and protein = 0.54 respectively). There were no apparent changes in GLP-2 levels with gestational or postnatal age. As a corollary to the correlation with bowel length, a postprandial level of 15 pmol/L appeared to be discriminatory; infants with postprandial GLP-2 levels of > 15 pmol/L were able to be weaned from total parenteral nutrition, while 3 of 4 infants who had GLP-2 levels less than 15 could not be weaned by one year. These results show that in infants with intestinal dysfunction, GLP-2 levels are correlated with residual small bowel length and nutrient absorption, and may be predictive of outcome. In contrast to adults with intact colon and SBS, infants with SBS and intact colon do not appear able to produce GLP-2 in response to feeding stimulation. Further studies are suggested to examine the ontogeny of the GLP-2 axis and the possible therapeutic role of GLP-2 supplementation.     

Enteral feeding reduces endothelial nitric oxide synthase in the caudal intestinal microvasculature of preterm piglets

The initiation of enteral feeding represents a challenge to the neonatal intestinal microcirculation, especially in preterms where it predisposes to necrotizing enterocolitis (NEC). We hypothesized that a structural microvascular deficiency may occur when enteral feeding is initiated in preterm piglets susceptible to NEC. Stereologic volume densities of a pan-endothelial marker (vWF), and the main vasodilator endothelial nitric oxide synthase (eNOS), were determined along the small intestine of 1) unfed preterm piglets, 2) piglets receiving total parenteral nutrition (TPN) for 2-3 d, and 3) piglets fed 2 d sow's colostrum (TPN+SOW) or milk formula (TPN+FOR) following TPN. In the mucosa, vWF-density decreased in a cranio-caudal direction. A corresponding mucosal eNOS gradient appeared only after initiating enteral feeding. In TPN+SOW, eNOS induction may lag behind the mucosal growth of the caudal region. In TPN+FOR, formula-related factors (i.e. bacteria, cytokines) may suppress mucosal eNOS, indicated by increased stress-sensitive nuclear HIF1alpha staining. The low mucosal endothelial eNOS density was related to the presence of NEC lesions, maybe via increased hypoxia-sensitivity, especially in the caudal region as indicated by nuclear HIF1alpha-staining. Our results suggest an insufficient structural adaptation of the microvasculature to enteral feeding, especially of mucosal eNOS, which may lead to NEC.     

Parenteral nutrition compared with transpyloric feeding.

Fifty nine infants of birthweight less than 1500 g were allocated alternately to initial total parenteral nutrition or to transpyloric feeding. Mortality was similar between the two groups. Ten of the 29 infants in the transpyloric group failed to establish full enteral nutrition during the first week of life. No beneficial effects on growth were shown in infants receiving parenteral nutrition. Acquired bacterial infection was higher in the parenteral group and associated with morbidity and mortality. Conjugated hyperbilirubinaemia occurred only in the parenterally fed infants. The incidence of necrotising enterocolitis was higher in the transpyloric group. Parenteral nutrition does not confer any appreciable benefit and because of greater complexity and higher risk of complications should be reserved for those infants in whom enteral feeding is impossible.     

Percutaneous gastrojejunostomy in children: efficacy and safety

Transgastric jejunal intubation via gastrostomy (GJ) can be indicated when enteral nutrition via gastrostomy is not possible. Between 2001 and 2008, the authors prospectively assessed the outcomes in 29 patients (median age, 10 months) after GJ. Indications for jejunal feeding were severe gastro-oesophageal reflux (n=27) and intestinal dysmotility (n=2). The GJ was successfully placed in 27/29 patients. Complications were: 31 tube dislodgements, 16 obstructions, 7 leakages around the tube, 6 internal balloon ruptures and 1 intussusception. The median lifetime of the tube was 3 months. 9/27 patients died during the study period, 11 patients required surgery, 2 required parenteral nutrition, gastric feeding became tolerated in 3 and the gastrojejunal feeding tube was kept in place in the remaining 2. A transgastric jejunal feeding tube may constitute a transitory alternative to antireflux surgery or prolonged parenteral nutrition. However, the high frequency of complications and tube replacement limits its use.     

Investigation of three doses of oral insulin-like growth factor-I on jejunal lactase phlorizin hydrolase activity and gene expression and enterocyte proliferation and migration in piglets

In a previous study, oral IGF-I at 65 nM increased lactase phlorizin hydrolase (LPH) activity and villus height in piglets, however, the mechanisms were unknown. Herein, the response to a range of doses of IGF-I was investigated and we hypothesized that LPH and villus height would respond to oral IGF-I in a dose-dependent manner. Two 14-d experiments were conducted using cesarean-derived piglets. In experiment 1, piglets (n = 28) were fed formula containing 0, 33, 65, or 131 nmol/L (0, 0.25, 0.5, or 1.0 mg/L) recombinant human IGF-I. In experiment 2, 5'-bromodeoxyuridine was administered to piglets fed formula alone (n = 4) or containing 131 nmol/L IGF-I (n = 4). IGF-I did not affect body weight gain or intestinal weight or length. Jejunal villus height and LPH activity were significantly greater in piglets fed 131 nmol IGF-I/L than control piglets. Villus height and lactase activity in piglets fed the 33 and 65 nmol/L IGF-I doses were similar and intermediate between control and 131 nmol IGF-I/L. Jejunal mRNA expression and LPH polypeptide abundance were investigated in piglets receiving 0 or 131 nmol/L IGF-I. Steady state LPH mRNA abundance was significantly higher (p < 0.05) in IGF-I-treated piglets. The relative abundance of proLPH(h) was not significantly increased (p = 0.06) by IGF-I treatment. Mucosal DNA content and DNA synthesis were greater in piglets receiving 131 nmol IGF-I/L than control, however, enterocyte migration and mucosal protein content were unaffected. Thus, oral IGF-I increased jejunal LPH activity and LPH mRNA abundance and stimulated intestinal cell hyperplasia in normal piglets.     

Gut Hormones and 'Minimal Enteral Feeding'

ABSTRACT. Previously we have identified multiple surges in plasma concentrations of gut hormones post-natally in enterally fed term and preterm infants. In this study on 104 preterm infants we have shown that such surges are induced after ingestion of very small quantities of human milk. Whereas 6-day-old exclusively parenterally fed infants showed no postnatal elevation in enteroglucagon, gastrin, GIP, motilin and neurotensin, infants recovering from hyaline membrane disease who had received restricted enteral nutrition had similar hormone surges to those seen in well infants on full enteral feeds. Significant elevations in enteroglucagon, gastrin and GIP occurred after a cumulative mean enteral feed volume since birth of only 24 ml (12 ml/kg body weight) had been consumed and after a mean total intake of 96 ml (50 ml/kg) the response was maximal. Greater feed volumes were required to produce a neurotensin or motilin surge, but even these volumes were substantially lower than those required for full enteral feeding. In view of the proposed roles of gut hormones in the adaptation to extrauterine nutrition these data have implications for mammalian biology and raise the possibility that 'minimal enteral feeding' might have a clinical therapeutic role in infants undergoing prolonged parenteral nutrition.     

Urinary lithogenic and inhibitory factors in preterm neonates receiving either total parenteral nutrition or milk formula

The aim of this study was to evaluate prospectively the influence of nutrition on certain factors which may inhibit or promote nephrocalcinosis in two groups of preterm infants, receiving total parenteral nutrition (TPN) and special preterm milk formula respectively, but not furosemide. A total of 37 preterm infants, 15 on TPN and 22 fed a special preterm formula were studied at the end of the 1st, 2nd and 3rd weeks of life, at which time serum and 8 h urine specimens were collected. High ratios of urinary calcium to urinary creatinine (UCa/cr), urinary oxalate to urinary creatinine (Uox/cr) and urinary calcium to urinary citrate (UCa/cit) indicates an increased risk for nephrocalcinosis while high urinary citrate to urinary creatinine (Ucit/cr) ratio indicates protection. Uox/cr increased significantly (P<0.05) in those infants fed preterm formula, from the end of 2nd week of life and was two-fold higher than in the TPN group of preterm infants (P<0.01). Ucit/cr was higher throughout the study period in the formula fed than in the TPN preterm infants. UCa/cit was five-fold higher (P<0.01) in the TPN group, by the end of the 3rd week. Urinary calcium and magnesium was similar in both groups during the study period. Two of the infants studied (5.4%), one from each group, developed nephrocalcinosis.CONCLUSION: In preterm neonates on total parenteral nutrition, urinary oxalate -to-creatinine ratio (a potent lithogenic factor) was lower and urinary citrate -to-creatinine ratio (a lithoprotective factor) also lower than in formula fed neonates. The type of feeding (total parenteral nutrition or special preterm milk formula) seems to affect urinary oxalate and citrate but not calcium and magnesium in non-furosemide treated preterm infants during the first 3 weeks of life.     

Erythromycin establishes early oral feeding in neonates operated for congenital intestinal atresias

Purpose  The recovery of gastrointestinal function following surgery for congenital intestinal atresias can be prolonged and may increase morbidity and hospital stay. This study was conducted to investigate the prokinetic effect of erythromycin in neonates undergoing surgery for small bowel atresias. Methods  A randomized-controlled trial was conducted at the Departments of Paediatrics and Paediatric Surgery, Military Hospital, Rawalpindi, Pakistan, from January to December 2007 to study the prokinetic effect of erythromycin (3 mg/kg per dose 4 times daily). Thirty consecutive neonates undergoing primary anastomosis for congenital small bowel atresias were randomly divided into two groups: group I (erythromycin) and group II (control). The groups were similar in terms of gestational age, sex, mode of delivery, birth weight and types of atresias. Postoperative recovery of intestinal functions was measured as time taken to achieve full enteral feed (150 ml/kg per 24 h), duration of total parenteral nutrition (TPN) and hospital stay. Results  Neonates receiving oral erythromycin achieved full enteral feeding early (13.07 vs. 16.13 days) required TPN for shorter duration (10.53 vs. 13.73 days) and their hospital stay was less (16.2 vs. 18.0 days) as compared to the neonates in the control group who did not receive any erythromycin. The differences were statistically significant. Conclusion  The administration of oral erythromycin following primary anastomosis for small intestinal atresias results in early recovery of intestinal function, fewer days on TPN and a trend for shorter hospital stay.     

Long-term home parenteral nutrition in pediatrics: ten years of experience in 102 patients

One hundred two pediatric patients received all or part of their nutritional needs parenterally at home during the past decade. All received total parenteral nutrition (TPN) at night during an 8- to 12-h infusion. Patients with short bowel syndrome (33%), inflammatory bowel disease (23%), chronic intractable diarrhea (15%), chronic idiopathic intestinal pseudo-obstruction syndrome (10%), and malignancy (10%) made up the largest groups. The mean duration of parenteral support was 735 days (range, 90-3650 days); the mean number of catheters per patient was 2.1 (range, 1-8). Twenty-one patients continue to receive full or partial home TPN: four for more than 10 years and seven for more than 5 years. Fifty-one no longer require it and have had healing of mucosa or bowel adaptation. Complications related to administration of fluid and electrolytes were quite rare. Biotin deficiency was recognized once. Thirty-one have died, but only 13 deaths were related to TPN. Sepsis in nine and liver failure in two were the most common causes of death in the TPN-related group. Three of 21 still on home TPN have graduated either from high school or college. All but one of the school age children attend regular school; one attends a school for the medically disabled, another attends a school for the mentally gifted.     

Effects of nutritional rehabilitation on intestinal function and on CD4 cell number in children with HIV

BACKGROUND: A complex interplay of malnutrition, intestinal dysfunction, and immune impairment increases the progression of human immunodeficiency virus (HIV) disease in children. The authors tested the hypothesis that nutritional support improves intestinal and immune functions in children infected with human immunodeficiency virus (HIV). METHODS: A questionnaire was circulated through reference centers for pediatric HIV infection to evaluate the effects of nutritional rehabilitation, total parenteral nutrition (TPN) and enteral nutrition (EN), in children. Information included changes in body weight, CD4 cell numbers, and intestinal absorption-as judged by the xylose load-before and after clinical nutritional support and the outcome of children. RESULTS: Sixty-two children underwent nutritional support: 46 received TPN and 16 received EN. All but three had full-blown acquired immunodeficiency syndrome, and all were severely malnourished. Baseline clinical conditions were worse in children receiving TPN than in those receiving EN. Intestinal dysfunction was detected in all children who received xylose oral load. A significant increase in CD4 cell count, xylose levels, and body weight followed EN. A similar pattern was observed after TPN, but none of the parameters significantly changed. Twenty-seven children who received TPN and three who received EN eventually died. Fourteen who received TPN and eight who received EN were shifted to oral feeding, and five who received TPN and five who received EN continued with clinical nutritional support at the end of the observation period. CONCLUSIONS: Nutritional intervention may restore intestinal absorption and increase CD4 cell numbers. The efficacy of nutritional intervention is enhanced if provided before a terminal stage of HIV infection. These data provide evidence of a close association among nutritional condition, intestinal absorption, and immune impairment.     

Enteral and parenteral nutrition in patients with short-bowel syndrome.

Short-bowel syndrome is functionally defined as a state of malabsorption following loss of small bowel. Most cases occur in the neonatal period after extensive resection for necrotizing enterocolitis, or due to congenital anomalies of the gastrointestinal tract. A smaller percentage originate later in life from surgical treatment of Crohn's disease, neoplastic disorders, or vascular events. The physiological, morphological and functional intestinal gradient determines the clinical picture leading to better tolerance of jejunal than ileal resections. The subsequent adaptation process requires enteral feeding with a different impact of specific nutrients, and is also influenced by a number of humoral mediators such as enteroglucagon, gastrin, growth factors, prostaglandins and polyamines. Nutritional management starts parenterally via a central venous line covering basic demands, substituting current losses and restoring pre-existing deficiencies. Continuous enteral tube feeding is added as soon as postoperative ileus resolves, beginning with an elemental diet, which is gradually increased first in concentration, then in quantity, and supplemented by small oral meals. Cycling of parenteral nutrition is the next step. As soon as sufficient stability is reached, the child should be discharged home under continued outpatient care. Main long-term problems comprise bacterial overgrowth, fluid and electrolyte disequilibration, nutritional deficiencies, parenteral nutrition-related liver disease, and central venous line complications such as sepsis and thrombosis.     

1例小肠唇状瘘、重度营养不良伴抑郁患儿的特殊分段肠内营养治疗

目的介绍1例车祸伤后小肠唇状瘘、重度营养不良伴抑郁患儿围手术期的临床营养专科管理方案。方法关瘘术前采用局部双腔套管负压引流,联合静脉使用生长激素及生长抑素,满足其经口进食欲望(限量半流质饮食),收集食物残渣后由瘘口排除,并通过远端空肠营养置管间歇输注个性化肠内营养液,实现分段肠内营养支持。关瘘术后逐渐恢复普通饮食。治疗期间利用儿童抑郁量表(children’s depression inventory,CDI)评估患儿的情绪及行为,积极辅以肠外营养支持,并持续监测患儿消化道情况、体重和营养相关生化指标,阶段性调整营养方案。结果患儿抑郁量表得分从31分降至14分,心理状态逐渐稳定,配合度逐渐提高,实现体重平稳增长,达到手术要求并顺利关瘘,行关瘘术后营养状况进一步改善,顺利出院。结论根据患儿心理特点和车祸伤后新的胃肠解剖结构,制定个性化的肠内肠外营养方案,可以保证患儿治疗依从性和治疗效果。     

Intestinal adaptation in pediatric patients with short-bowel syndrome.

The purpose of this study is to evaluate 12 pediatric short-bowel syndrome (SBS) patients experienced at Osaka University Hospital and its affiliated hospitals and to study the intestinal length for achieving intestinal adaptation and the metabolic characteristics. The length of the residual small intestine ranged from 0 to 75 cm with an average of 47 cm and an ileocecal valve had been resected in five cases. Total parenteral nutrition (TPN) was started immediately after operation and was gradually substituted by enteral nutrition. No patient died during the follow-up period. Eight of 12 patients could be weaned from TPN with residual intestinal length of 27 to 75 cm (mean 57 cm). Four patients with the residual intestine of 0 to 45 cm (mean 22 cm) were unable to achieve intestinal adaptation. The rate of catheter-related sepsis per 1000 catheter days was 0.63. Fatty liver was detected in two cases, but no patient developed progressive liver failure. Plasma arginine and citrulline were decreased in patients who were unable to achieve intestinal adaptation. Our nutritional support program provided excellent survival for pediatric SBS patients primarily due to the low incidence of catheter-related sepsis and no episode of severe liver disease. Patients with more than 16 cm of residual intestinal length can be expected to be weaned from TPN.     

Enteral feeding in utero induces marked intestinal structural and functional proteome changes in pig fetuses

Intestinal adaptation from parenteral to enteral nutrition is crucial for survival and growth of newborns. Rapid feeding-induced gut maturation occurs immediately after birth in both preterm and term neonates, but it remains unclear whether the responses depend on factors related to birth transition (e.g. bacterial colonization, endocrine, and metabolic changes). We hypothesized that enteral feeding matures the immature intestine, even in fetuses before birth. Hence, control pig fetuses were compared with fetuses fed with milk formula for 24 h in utero. Gel-based proteomics showed that feeding-induced changes in 38 proteins, along with marked increases in intestinal mass and changes in activities of brush border enzymes. Physiological functions of the identified proteins were related to enterocyte apoptosis (e.g. caspase 1) and nutrient metabolism (e.g. citric acid cycle proteins). Many of the differentiated proteins were similar to those identified previously in preterm pigs fed with the same formula after birth, except that effects on proteins related to inflammatory lesions (e.g. heat shock proteins) were absent. Our results show that enteral feeding, independently of the birth transition, induces marked gut maturation and proteome change in the immature intestine. Hence, immediate postnatal feeding-induced gut changes are largely independent of factors related to the birth transition.     

中国新生儿营养支持临床应用指南

该指南目的是建立能够反映当前最佳临床实践,循证的营养支持指南,为临床实践和进一步的临床研究方向提供参考。该指南参考了大量已发表的相关文献,在此基础上,由来自各相关学科的多位专家起草、审阅并反复修改而成。目标人群为早产儿、低体重出生儿等危重新生儿。指南分为肠内营养、肠外营养、肠内肠外营养联合应用三部分。当经口喂养无法满足患儿需要量时,应给予肠内或肠外营养支持。如果患儿存在胃肠道功能障碍,肠外营养是唯一选择。指南最后给出了肠内肠外营养联合应用的计算公式。     

Report of three cases: congenital chylothorax and treatment modalities

Chylothorax is the most common cause of pleural effusion in the newborn. We report three patients with congenital chylothorax and discussed the clinical course and treatment options. Cases 1 and 2 with congenital chylothorax were treated by chest tube placement and total parenteral nutrition (TPN), and were fed a formula rich in medium-chain triglyceride. They were discharged home without any sequelae. Our 3rd case with chylothorax did not respond to the conventional therapies. Octreotide infusion was tried without any benefits and necessitated surgical intervention, but the infant developed chronic lung disease requiring nasal oxygen therapy until three months of age. All three patients developed complications of chylothorax treatment like chest tube dysfunction, pneumothorax, nosocomial sepsis, and cholestasis. Management of congenital chylothorax necessitates a multidisciplinary approach. Treatment options include pleural drainage, cessation of enteral feeding and initiation of TPN. Experience with octreotide treatment is limited. Surgery should be reserved for severe and refractory cases.