Erythropoietin acts as a trophic factor in neonatal rat intestine.

BACKGROUND: Erythropoietin (Epo) receptors are present on enterocytes of fetal and neonatal small bowel but the role of Epo in the bowel is not known. AIMS: We tested the following hypotheses: (1) enterally dosed Epo is absorbed from the intestines of neonatal rats, (2) Epo acts as a trophic factor in developing small bowel, and (3) the trophic effects of Epo are dependent on the route of administration. METHODS: The dose dependent effects of enterally dosed recombinant human erythropoietin (rEpo 0--1000 U/kg/day) were studied in artificially raised rat pups and compared with dam raised controls and dam raised pups given rEpo in rat milk. After one week, reticulocyte counts, haematocrits, and plasma Epo concentrations were measured, and calibrated morphometric measurements of villi were performed. The effects of route of rEpo administration (enteral v parenteral) on erythropoiesis, bowel growth, and disaccharidase activity were studied in nursing pups treated for one and two weeks. RESULTS: Serum Epo concentrations ranged from undetectable (<0.6 mU/ml) to 8.4 mU/ml in control and enterally dosed pups (median 1.8 mU/ml), and from 4.9 to 82.3 mU/ml (median 20.4 mU/ml) in parenterally dosed animals. No increase in haematocrit or reticulocyte count was noted in enterally treated pups compared with controls after up to two weeks of treatment. Small bowel length was greater in rEpo treated pups, and a dose dependent increase in villus surface area which was independent of the route of dosing and associated with increased BrdU uptake was found. CONCLUSIONS: rEpo is not enterally absorbed in an intact and functional form from the intestines of neonatal rat pups. Thus enterally dosed rEpo has no erythropoietic effects. However, rEpo acts as a trophic factor in developing rat small bowel whether given enterally or parenterally.

Necrotizing enterocolitis and hematopoietic cytokines.

The names of the hematopoietic cytokines are misleading because in addition to their effects on bone marrow and bone marrow-derived cells, they have many diverse effects, including effects on the gastrointestinal tract. These effects may be directly mediated by interaction with specific receptors on gastrointestinal epithelial cells, or they may result from their effects on circulating or bowel wall leukocytes and the cytokines these cells produce. As might be expected of factors largely defined by their effects on inflammatory cells, the hematopoietic cytokines are intimately involved in the processes of bowel injury. Further investigations are needed to define the role of hematopoietic cytokines in the human neonate's balance between local gastrointestinal host defense and bowel wall injury. This could lead to effective strategies for the treatment and prevention of NEC.

Erythropoietin and the incidence of necrotizing enterocolitis in infants with very low birth weight.

BACKGROUND/PURPOSE: The presence of erythropoietin (Epo) in human milk and the expression of Epo receptors on intestinal villous enterocytes of neonates suggest that Epo has a role in growth and development of the gastrointestinal tract. On this basis, the authors hypothesized that recombinant Epo (rEpo) given for prevention or treatment of the anemia of prematurity would protect against necrotizing enterocolitis (NEC). METHODS: A retrospective cohort study was conducted from a university neonatal intensive care unit of 483 very low birth weight (500 to 1,250 g) neonates born from July 1, 1993 to January 1, 1998. RESULTS: A total of 260 neonates received rEpo, and 223 did not (control group). The rEpo and control groups were similar in gender distribution (52% v. 48% boys), gestational age (26.8+/-2.1 v. 27.6+/-2.9 weeks; mean +/- SD), birth weight (895+/-198 v. 911+/-208 g), 1 and 5 minute Apgar scores (4.2 and 6.1 v4.7 and 6.7), and incidence of severe intraventricular hemorrhage (8.9% v. 10.3%). The rEpo group had a lower incidence of NEC (12 of 260, 4.6% v. 24 of 223, 10.8%; P = .028, 95% confidence interval for difference: -0.108 to -0.015). CONCLUSION: In very low birth weight infants, the incidence of NEC is lower in those who received rEpo.

Detrimental effects of standard medical therapy in congenital diaphragmatic hernia.

OBJECTIVE: To evaluate the impact of a nonstandard ventilation strategy on survival in congenital diaphragmatic hernia (CDH). BACKGROUND: Despite recent advances, including nitric oxide, CDH remains an unsolved problem with a mortality rate of 35% to 50%. Hyperventilation and alkalization remain common therapies. METHODS: In 1992, the authors prospectively abandoned hyperventilation and alkalization. Patients are lightly sedated and ventilated with the lowest pressure providing adequate chest movement, and the rate is set to patient comfort. Nitric oxide and extracorporeal membrane oxygenation (ECMO) are reserved for life-threatening instability. Surgical repair is delayed 1 to 5 days. Sixty consecutive patients are compared with 29 previous patients treated with hyperventilation and alkalization, 13 before and 16 after the availability of ECMO. RESULTS: Overall, 47 of 60 patients (78%) in study era 3 survived compared with 2 of 13 (15%) in the hyperventilation era and 7 of 16 (44%) in the hyperventilation/ECMO era (p < 0.0001). The disease severity and the incidence of associated anomalies did not differ between groups. To compare management strategies, patients who had treatment withheld because of lethal associated conditions were then removed from analysis. Peak inspiratory pressure and arterial pH were lower (p < 0.0001) and Paco2 was higher (p < 0.05) in era 3 than in the previous eras. The rate of pneumothorax (1.9%) decreased (p < 0.0001). In era 3, survival was 47 of 53 (89%) treated patients, and 23 of 25 inborn patients with isolated CDH survived (92%). CONCLUSIONS: Nonstandard ventilatory support of patients with CDH has led to significantly improved survival rates. This study sets a survival benchmark and strongly suggests the negative effects of hyperventilation and alkalization.

Why is erythropoietin present in human milk? Studies of erythropoietin receptors on enterocytes of human and rat neonates.

Erythropoietin receptors (Epo-R) are expressed on cells in the small bowel of human fetuses, but their function has not been defined. We hypothesized that intestinal Epo-R are present postnatally, and that recombinant erythropoietin (rEpo) would increase enterocyte migration and decrease cytokine-induced apoptosis. We used reverse transcriptase-polymerase chain reaction and immunohistochemistry to evaluate the presence of Epo-R mRNA and protein in rat intestinal epithelial cells (IEC-6), and in postnatal human and rat bowel. The effect of rEpo on rates of cell migration and proliferation were established in IEC-6 cells by using cell counting and incorporation of bromodeoxyuridine. To determine whether rEpo affects response to injury, cells were pretreated with rEpo, then were damaged with 25 or 50 ng/mL tumor necrosis factor-alpha plus 2.5 microg/mL cycloheximide. Cell death was determined by colorimetric bioassay. We found that Epo-R mRNA and protein were expressed by IEC-6 cells and by enterocytes of postnatal rat and human small bowel. Cells that had been exposed to 0.05 or 5.00 U/mL rEpo migrated faster than did the controls (p < 0.05), but no difference was noted in cell proliferation. Treatment of IEC-6 cells with rEpo before or at the time of injury resulted in a lower percentage of cell death, and this effect was neutralized by anti-Epo antibody. We conclude that Epo-R is expressed in enterocytes postnatally in rats and humans. Recombinant Epo increases the rate of migration of IEC-6 cells and decreases cytokine-induced apoptosis. These studies suggest that Epo within human milk has actions on neonate's intestinal function.

Congenital diaphragmatic hernia. Epidemiology and outcome.

Congenital diaphragmatic hernia is a relatively common birth defect. It affects about 1114 babies a year in the United States. Reported survival averages 60% but may be significantly lower. We do not understand the etiology of CDH. Its association with other anomalies and several distinct patterns of presentation suggest that more than one cause may exist. There is a high degree of variability in both treatment and outcomes, but no data exist to allow a rigorous comparison of the efficacy of various treatment strategies. Stratification of patients into more homogeneous groups will be a necessary prerequisite for the design of meaningful comparative trials. The incidence of the lesion prevents any single institution from accruing sufficient patients to conduct such a trial. An ad hoc multicenter study group (the Congenital Diaphragmatic Hernia Study Group) has been formed for this purpose. This organization has begun collecting data with an initial goal of developing a stratification scheme. Prospective data collection should allow verification of several of the estimates made in this article. Current data make it clear that CDH represents a major cause of perinatal morbidity and mortality.

Traumatic arteriovenous fistula: a complication of amniocentesis.

Fetal injury is a potential complication of amniocentesis. We report the case of an infant who had an isolated arteriovenous fistula between the popliteal artery and vein that resulted from amniocentesis. Unlike the usual congenital arteriovenous communications that are multiple and difficult to treat, this case was completely cured by division of the fistula and vascular repair. This case emphasizes that newborns and infants who have had invasive prenatal interventions such as amniocentesis should be identified and the possibility of fetal injury be considered when evaluating their clinical signs and symptoms.

Necrotizing enterocolitis in term neonates.

Necrotizing enterocolitis (NEC) is usually a disease of premature infants, but occasionally it affects the term neonate. A 5-year review of NEC at Children's Hospital and Medical Center identified the unique features of this disease in the term neonate. Eighty-one patients with NEC were treated between January 1984 and May 1989. Ten full-term neonates with gestational age greater than 38 weeks were identified for study. Charts were reviewed for recognized risk factors, clinical course, surgical intervention, and outcome. Ninety percent had a birth weight greater than or equal to 2.7 kg, and all were above 2.1 kg. NEC developed early in this group, with onset of disease in the first 48 hours of life in 50% of the group and within the first 4 days of life in 90%. The recognized risk factors of asphyxia, hypoglycemia, polycythemia, and respiratory distress were absent in 60%. Seven of 10 patients required exploratory laparotomy, whereas 3 of 10 required only medical treatment. Indications for operation were perforation in three patients, peritonitis in three patients, and mass in one patient. All patients requiring operations had severe colonic disease, with perforation of the colon in five of seven and full-thickness necrosis without perforation in two of seven. Two patients required total abdominal colectomy. Only one patient with perforated meconium ileus and associated NEC had small bowel involvement. This patient was the only mortality of the group. Subsequent intestinal continuity was restored in all surviving patients with no late complications. Two patients required resection of additional NEC strictures prior to reanastomosis. Of the three medically treated patients, none required subsequent operation for colonic stricture. Our experience indicates that the presentation, clinical course, and operative findings in full-term neonates with NEC differ from those encountered in the premature infant with NEC.

Diagnostic and surgical implications of child abuse.

One hundred fifty-six children younger than 13 years of age with blunt abdominal injuries were reviewed, and those injured in accidents (89%) were compared with those injured by child abuse (11%). Abused children were younger (mean age, 2 1/2 years) and all presented late to medical attention with a history that was inconsistent with their physical findings. Only 65% of abused children had physical or roentgenographic signs of prior abuse, while 35% had no signs of prior abuse. The abdominal organs injured were different; 61% of accidentally injured children suffered injuries to a single, solid organ, and only 8% had hollow viscus injuries, while 65% of abused children had hollow viscus injuries. Physicians should suspect child abuse when children have unexplained injuries (especially young children with hollow viscus injuries) even when other signs of child abuse are absent, and they should suspect hollow viscus injury in abused children.

Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas.

The development of serotonergic innervation to rat cerebral cortex was characterized by immunohistochemical localization of serotonin combined with autoradiographic imaging of serotonin-uptake sites. In neonatal rat, a transient, dense, serotonergic innervation appears in all primary sensory areas of cortex. In somatosensory cortex, dense patches of serotonergic innervation are aligned with specialized cellular aggregates called barrels. The dense patches are not apparent after 3 weeks of age, and the serotonergic innervation becomes more uniform in adult neocortex. This precocious neonatal serotonergic innervation may play a transient physiologic role in sensory areas of cortex or may exert a trophic influence on the development of cortical circuitry and thalamocortical connections.