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An outbreak of necrotizing enterocolitis. Association with transfusions of packed red blood cells.

Of 187 newborns admitted to a 33-bed, level III neonatal intensive care unit between January 1, 1985 and June 23, 1985, 33 developed necrotizing enterocolitis during their hospital stay. Twenty of the 33 newborns (61%) had onset of symptoms between April 1 and June 23, suggesting clustering during this period. A case-control study, with matching on birth weight class, approximate date of admission to the unit and approximate duration of stay, failed to reveal any association of the syndrome with type or timing of feeding, perinatal hypoxic events, as determined by apgar scores and labor history, or specific microbial organisms. By contrast, however, transfusion of packed red blood cells was highly and significantly associated with the syndrome (odds ratio = 15.1, 95% confidence interval = 2.59-92.51). In addition, therapy with caffeine, with theophylline, and with furosemide were moderately associated with the syndrome, although not significantly so. During this outbreak period, the incidence of necrotizing enterocolitis by birth weight was 30.6% in infants less than 1,500 gm, 10.8% in infants 1,500-2,500 gm, and 11.9% in infants 2,500 gm or more. These findings confirm the importance of low birth weight as a risk factor for development of the syndrome and suggest that insults to volume homeostasis, such as transfusion and use of diuretics, need to be considered as possible mechanisms whereby necrotizing enterocolitis is initiated.

Birth Weight↗

The role of polyunsaturated fatty acid supplementation in intestinal inflammation and neonatal necrotizing enterocolitis.

Dietary polyunsaturated fatty acid (PUFA) supplementation has been shown to reduce the incidence of necrotizing enterocolitis (NEC) in a recent randomized, controlled trial. These compounds are known to modulate the inflammatory cascade and to influence intestinal health in a variety of ways. Although the pathophysiology of NEC is not well understood, recent evidence suggests that platelet-activating factor (PAF) is a key endogenous mediator of intestinal necrosis in animals. Using a neonatal rat model of NEC that includes the key risk factors of asphyxia and formula feeding, we investigated the role of dietary PUFA supplementation on the incidence and pathophysiology of NEC. Our findings suggest that PUFA reduce the incidence of NEC by modulating PAF metabolism and endotoxin translocation.

Animals↗

Diminished epidermal growth factor levels in infants with necrotizing enterocolitis.

BACKGROUND/PURPOSE: Because epidermal growth factor (EGF) is trophic to the intestinal mucosa, and neonatal necrotizing enterocolitis (NEC) is associated with a disrupted intestinal mucosal barrier, the authors sought to determine whether diminished levels of EGF were present in infants with NEC. METHODS: Saliva, serum, and urine specimens were obtained from infants with NEC during a 3-year period (February 1995 to May 1998). Control patients without NEC were chosen based on similar postnatal age and birthweight. EGF levels were determined by enzyme-linked immunosorbent assay (ELISA). Differences between groups were compared using Mann-Whitney Rank sum test with P less than .05 considered significant. Results are presented as mean values +/-SEM. RESULTS: Twenty-five infants with NEC were compared with 19 control patients. Birth weight (1,616+/-238 g control v. 1,271+/-124 g NEC) and postnatal age (23+/-6 days control v. 22+/-3 days NEC) were similar. Infants with NEC had significantly lower levels of EGF in both saliva (590+/-80 pg/mL control v. 239+/-41 pg/mL NEC; P<.001) and serum (35+/-8 pg/mL control v. 5.6+/-1.9 pg/mL NEC; P<.001). Urinary EGF was also lower in the NEC group, but was not statistically significant. CONCLUSIONS: Premature infants with NEC have significantly diminished levels of salivary and serum EGF. Reduced levels of this growth factor may distinguish infants at risk for NEC and play a pivotal role in the pathogenesis of the perturbed intestinal mucosal barrier that is central to this condition.

Enterocolitis, Necrotizing↗

Impact of gestational age on the clinical presentation and surgical outcome of necrotizing enterocolitis.

OBJECTIVE: This investigation tests the hypothesis that the clinical presentation and the outcome of necrotizing enterocolitis (NEC) vary with gestational age (GA). METHODS: All infants admitted to our center between October 1991 and September 2003 were evaluated weekly to identify confirmed cases of NEC. Based upon GA, these infants were divided into five groups: Extremely premature (EP, 23 to 26 weeks), very premature (VP, 27 to 29 weeks), moderately premature (MP, 30 to 34 weeks), near-term (NT, 35 to 36 weeks), and term (T, 37 to 42 weeks). RESULTS: A total of 202 infants developed NEC. The most common sign of NEC among EP infants was ileus (77%), followed by abdominal distention (71%), emesis (58%), pneumoperitoneum (54%), fixed intestinal loop (52%), gasless abdomen (42%) and bloody stools (17%). Intramural gas was detected in 100% of T but was present in only 29% of EP infants (P < 0.0001). Similarly, portal venous gas was common in T but infrequent in the EP infants (47 vs 10%, P < 0.0001). Despite a higher peritoneal drain insertion rate (31 vs 5%, P < 0.001) and a higher mortality rate (33 vs 10%, P = 0.05) in EP compared to T infants, other clinical outcomes were not different. CONCLUSIONS: The clinical presentation of NEC is different in EP compared to more mature infants; however, outcome among NEC survivors is similar across all GA. Reliance solely on observation of intramural or on portal venous gas in EP infants may lead to a delay or failure in the diagnosis.

Enterocolitis, Necrotizing↗

Potential prophylactic value of bovine colostrum in necrotizing enterocolitis in neonates: an in vitro study on bacterial attachment, antibody levels and cytokine production.

Necrotizing enterocolitis (NEC) is an important disease of low birth-weight neonates. The immaturity of the gut mucosa may result in close contact between the host epithelium and microorganisms which are normally confined to the gut lumen. Damage of the mucosa due to endotoxin, cytokine production or other factors is believed to then occur. The aim of this study was to determine whether spray-dried bovine colostrum demonstrated potential in vitro as a prophylactic for NEC. Antiadherence was measured using a tissue culture assay and antibody levels against Enterobacteriaceae were determined by ELISA. The effect of bovine colostrum on the production of cytokines implicated in NEC was determined by a multiplex bead assay. Enterobacter cloacae, Klebsiella oxytoca, Escherichia coli, Serratia marcescens and Klebsiella pneumoniae ssp. pneumoniae were common in both NEC positive and NEC negative infants and IgA and IgG1 antibodies to these species were present in the bovine colostrum. Pretreatment with bovine colostrum produced a significant decrease (P<0.001) in attachment of bacteria to HT-29 cells. Bovine colostrum significantly increased the production of IL-8 in HT-29 cells and IL-8, IL-6 and TNF-alpha in THP-1 cells (P<0.001). The potential of bovine colostrum to increase the production of inflammatory mediators could limit its usefulness.

Animals↗

[Nonocclusive intestinal infarct and necrotizing enterocolitis in the adult].

A case of full-thickness necrosis of the small bowel, and colon, which required partial resection of the jejunum and total resection of the ileum and colon is reported. The case gives the chance for a review of the Literature on intestinal necrosis not caused by vascular occlusion. Nonocclusive intestinal ischemia, acute neonatal necrotizing enterocolitis and adult necrotizing enterocolitis including the Pig-bel disease, common in Papua-New Guinea, are examined. Resemblances and differences in etiology, pathophysiology and clinical findings are discussed. The hypothesis that the process of "bacterial translocation" plays a central role in the pathogenesis of bowel infarction, representing therefore a possible link between infective and vascular mechanisms, is emphasized. Important suggestions on massive intestinal necrosis management are also reported.

Acute Disease↗

[Necrotizing enterocolitis: symptomatology, diagnosis and therapeutic consequences].

Within a 6-year period ten patients with necrotizing enterocolitis (grade II-III; Bell) have been treated at the University Hospital, Göttingen. The following NEC incidences were calculated: birth weight < 1000 g: 2.4% (3/123); 1000-1500 g: 0.6% (2/308); 1501-2000 g: 0.7% (3/436); > 3000 g: approximately 0.006% (2/30,000 live births). In all patients onset of necrotizing enterocolitis (NEC) was associated with typical clinical symptoms such as abdominal distension, feeding problems, bloody stools. Only four out of ten patients had positive blood tests of various inflammatory parameters when diagnosed (C-reactive protein, neutrophil count, I/T-ratio). However, increased CRP levels were observed in all patients during the course of the disease (maximum levels: day 2-4 after diagnosis). During primarily conservative therapeutic management only one out of ten patients developed bowel perforation (day 6 after diagnosis) and immediate surgical treatment was carried out. In addition, in three patients who acquired strictures with obstruction of the colon, elective surgery was performed at a postnatal age of 51-77 days. All patients survived NEC without longterm sequelae. We conclude that a primarily conservative therapeutic regimen-whenever perforation and gangrene are absent-may be an alternative to early surgical intervention in NEC.

Anastomosis, Surgical↗

[Determination of hydrogen in expiratory air of premature infants in suspected necrotizing enterocolitis].

BACKGROUND: Breath hydrogen (H2) analysis has been recommended for the differential diagnosis between necrotizing enterocolitis and transient feeding intolerance. METHODS: We performed 360 breath H2 analyses in 32 unselected premature babies by use of an electrochemical method. RESULTS: All babies on oral feedings excreted H2. The concentration of H2 in expired air was extremely variable and often high even in well premature babies. Antibiotic medication (other than penicillin G alone) inhibited breath hydrogen excretion. CONCLUSIONS: Breath hydrogen analysis can be used as a diagnostic tool for necrotizing enterocolitis if performed in a symptomatic child on oral feedings prior to the initiation of antibiotic therapy.

Birth Weight↗

Cow's milk intolerance presenting as necrotizing enterocolitis.

Case history is reported of an infant who was changed from breast to bottle feeding at fourth day of life, who on ninth day developed bilious vomiting and bloody diarrhoea. Later gas was found in colonic wall on X-ray. Necrotizing enterocolitis was diagnosed and infant managed with total intravenous alimentation. On recovery although she tolerated breast milk, return to cow's milk formula lead to return of bloody diarrhoea. Subsequently she thrived on a cow's milk-free diet based on chicken meat formula. At four months after total of 15 ml cow's milk she had an acute anaphylactic reaction. She recovered and is well on milk-free diet. Thus, this infant has recovered from necrotizing enterocolitis but has evidence of persistent cow's milk protein intolerance. The hypothesis is put forward that in this child cow's milk protein played a major role in the pathogenesis of necrotizing enterocolitis.

Animals↗

Surgical intervention in necrotizing enterocolitis in neonates with symptomatic congenital heart disease.

The commonly accepted indication for surgical intervention in necrotizing enterocolitis (NEC) is perforation of the bowel. In this study, the indication and role of surgery was assessed in neonates born with symptomatic congenital heart disease (CHD). Records of neonates admitted to a single institution in Hong Kong between January 1981 and December 1997 with symptomatic CHD who subsequently developed NEC were reviewed. The patients were categorized into cyanotic and acyanotic groups. Of 850 neonates with CHD admitted during the period, 30 developed NEC (3.5%); 17 had cyanotic and 13 had acyanotic heart disease. The average Apgar scores at 1 and 5 min were 7.5 and 8.6, respectively. The mean gestational age was 37.7 weeks and the mean birth weight was 2.5 kg. The mean age at which NEC developed was 16 days. The overall mortality in the proven cases of NEC was 57%. After excluding the suspected NEC cases (stage I), it was found that surgery in the proven NEC cases without perforation, i.e., stages II and IIIA, resulted in higher survival than in those managed medically (75% vs 44%). The cyanotic patients had higher mortality than the acyanotic group (71% vs 39%). Neonates with CHD who develop NEC belong to a unique group of mature babies with reasonable birth weights and Apgar scores, unlike the common NEC patient population. The mortality of these patients is extremely high, and a modified management approach is required. Surgical intervention may be indicated at a much earlier stage of proven NEC before gut perforation occurs.

Enterocolitis, Necrotizing↗

Ileoileal intussusception and ileal stricture associated with necrotizing enterocolitis in a premature infant: report of a case.

A 630-g male infant developed presumed necrotizing enterocolitis (NEC) after fungal enteritis that resulted in subsequent fungal septicemia associated with pneumoperitoneum on the 9th day of life. Urgent percutaneous Penrose drainage was required. During the operation on the 14th day, an ileoileal intussusception and an ileal stricture were found with perforations on each oral side of the lesions. The distinction between NEC and intussusception in premature infants when they coexist can be difficult, as these conditions share common symptoms. The relation between ischemic injury and dysmotility of the intestine is also discussed. The similarity of intrauterine fetal distress and NEC in premature infants, as seen in the present case of the intussusception associated with focal NEC, suggests that mesenteric and enteric vascular ischemia could be one trigger of intussusception in neonates.

Diagnosis, Differential↗

The role of peritoneal drains in treatment of perforated necrotizing enterocolitis: recommendations from recent experience.

BACKGROUND/PURPOSE: Intraperitoneal drains have been used in the treatment of perforated necrotizing enterocolitis (NEC), especially in infants less than 1,000 g, yet their role is still debated. The authors wished to examine their more recent experience in the treatment of NEC to make recommendations for operative management. METHODS: The authors reviewed the records of all infants seen between 1989 and 1995 who had clinical and radiological evidence of NEC at the Hospital for Sick Children, Toronto, Ontario. One hundred sixty-seven infants were treated for NEC and 73 (44%) infants required surgical intervention. RESULTS: Forty-five patients had perforated NEC; 23 were treated initially by peritoneal drainage and 22 by primary laparotomy. The 23 newborns who had peritoneal drainage were of significantly lower birth weight, and 19 (83%) of these infants required subsequent laparotomy for worsening disease. The overall mortality rate for perforated NEC was 36%. CONCLUSION: Insertion of a peritoneal drain is still useful in resuscitating small critically ill infants with NEC; however, the majority of these infants will also require laparotomy.

Drainage↗

Laparotomy for necrotizing enterocolitis: intensive care nursery compared with operating theatre.

OBJECTIVE: To determine whether neonates requiring laparotomy for necrotizing enterocolitis (NEC) are more stable perioperatively and have less disruption of physiological parameters if surgery is performed in the neonatal intensive care unit (NICU) compared with the operating theatre (OR). METHODOLOGY: A retrospective case review was performed on 233 neonates referred for further surgical management of severe NEC in the period January 1989 to December 1997. Mortality and morbidity were compared by calculating the score for neonatal acute physiology (SNAP) and its attendant risk of mortality score. Thirty-six separate physiological variables were also compared pre- and postoperatively and the mean postoperative change was calculated. RESULTS: For neonates weighing less than 1500 g, mortality was linked to illness severity, as measured by SNAP, rather than operative location. Specific adverse events associated with secondary transfer to the OR included hypothermia, deterioration in oxygenation parameters, ventilation parameters and platelet count. The liberal use of blood products, albumin and bicarbonate in perioperative resuscitation may have obscured other effects. CONCLUSIONS: The use of the neonatal intensive care nursery for surgery on neonates weighing less than 1500 g with severe NEC can be justified and such use should be encouraged. In contrast, secondary transport of neonates weighing less than 1500 g to the OR for laparotomy is associated with significant deterioration in a number of physiological parameters, which may impact on morbidity.

Enterocolitis, Necrotizing↗

Supplementation with Saccharomyces boulardii ameliorates hypoxia/reoxygenation-induced necrotizing enterocolitis in young mice.

Intestinal bacterial proliferation is an important aspect of gastrointestinal injury in neonatal necrotizing enterocolitis (NEC). In the present investigation, we examined the protective action of oral supplementation with Saccharomyces boulardii (S. boulardii), non-pathogen probiotic yeast, against hypoxia-reoxygenation (H/R)-induced NEC in young mice. Young mice were divided into three groups; Group 1 mice (untreated) were subjected only to hypoxia-reoxygenation; Group 2 mice were subjected to hypoxia-reoxygenation and were then given lyophilized S. boulardii (10 mg suspended in 0.5 ml saline) twice a day by orogastric intubation for 10 days. Group 3 mice served as controls. Hypoxia was induced by placing young mice in a 100 % CO (2) chamber for 5 min. After hypoxia, the young mice were reoxygenated for 10 min with 100 % oxygen. We examined the intestinal lesions by light microscopy and measured intestinal generation of PAF and TNF-alpha in the H/R-induced model of NEC. In the probiotic group, NEC-induced intestinal tissue damage was greatly attenuated, with necrosis partially limited to the mucosa. Both intestinal tissue PAF and TNF-alpha concentrations were significantly higher in the untreated group than in controls (p < 0.001). S. boulardii-supplemented young mice showed a significant decrease in intestinal generation of PAF compared with untreated young mice (p < 0.05). On the other hand, no significant difference was observed in the intestinal concentration of TNF-alpha between untreated and probiotic groups ( p > 0.05). The present study suggests that hypoxia/reoxygenation plays an important role in the pathogenesis of NEC and supports hypothesis that especially PAF and TNF-alpha are involved in the pathophysiological mechanism of H/R-induced NEC. This study also demonstrates that dietary supplementation with S. boulardii ameliorates the histologic evidence of H/R-induced intestinal injury. Based on these findings, the beneficial effects of probiotic S. boulardii in this model of NEC are mediated via mechanisms inhibiting intestinal proinflammatory mediator release.

Animals↗

Feeding strategies and necrotizing enterocolitis.

PURPOSE OF REVIEW: To update clinical trials concerning feeding strategies or feeding interventions to prevent necrotizing enterocolitis (NEC). RECENT FINDINGS: The overall incidence of NEC remains unchanged. Several studies have shown that it is safe to use small feeding volumes early in life even in selected circumstances, such as feeding during the use of indomethacin to treat symptomatic patent ductus arteriosus. Although descriptive case reports have linked some feeding interventions such as thickened feedings to NEC, there is no evidence to establish a causal relation. Interestingly, one report showed that neither the presence of-nor characteristics of-gastric residuals was helpful to identify those infants who subsequently develop NEC. Numerous studies in animals show that vascular and host defense responses are not adequate in the immature gut. A few small clinical trials showed that various feeding strategies may alter these responses in preterm infants. However, larger clinical trials around these issues await further characterization of the mechanisms that regulate these two aspects of gastrointestinal function with respect to feeding. SUMMARY: Studies continue to demonstrate how fragile the immature gut is, but further work directed to understanding the mechanisms that regulate gastrointestinal responses to feeding is needed to design meaningful interventions for large prospective trials.

Clinical Trials as Topic↗

Protective effect of dietary supplementation with L-arginine and L-carnitine on hypoxia/reoxygenation-induced necrotizing enterocolitis in young mice.

Oxygen-derived free radicals are important components of gastrointestinal injury in necrotizing enterocolitis (NEC). In the present investigation, we examined the protective actions of L-arginine, a nitric oxide synthase substrate, and L-carnitine against hypoxia-reoxygenation (H/R) induced NEC in young mice. Young mice were divided into four groups: group 1 mice were subjected to H/R only; group 2 H/R mice were supplemented with L-arginine in the drinking water (2 g/l) for 7 days; group 3 H/R mice were given L-carnitine solution in water (50 mg/kg p.o.) for 7 days, and group 4 mice served as controls. Hypoxia was induced by placing the mice in a 100% CO(2) chamber for 5 min. After hypoxia, the mice were reoxygenated for 10 min with 100% oxygen. We examined the intestinal lesions by light microscopy and measured the intestinal generation of thiobarbituric acid reactive substances (TBARS) and the activities of superoxide dismutase and catalase in the H/R-induced model of NEC. In both L-arginine and L-carnitine groups, the NEC-induced intestinal tissue damage was greatly attenuated, with necrosis limited partially to the mucosa. The tissue TBARS level was significantly higher in group 1 than in any of the other groups (p < 0.001). However, those treated with L-arginine and L-carnitine had TBARS levels similar to those in the control animals. An increased tissue concentration of nitrate, a stable metabolite of nitric oxide, was found in the L-arginine-supplemented group as compared with the control group (p < 0.05). Both superoxide dismutase and catalase activities in the intestine were similar in H/R groups when compared with the intestine of control animals. The present study suggests that oxygen-derived free radicals are involved in the pathogenesis of H/R-induced NEC. This study also shows that dietary supplementation with L-arginine and L-carnitine ameliorates the histological evidence of H/R-induced intestinal injury and significantly decreases lipid peroxidation in H/R-induced bowel injury. Based on these findings, the beneficial effects of L-arginine and L-carnitine in this model may be mediated via mechanisms preventing free radical damage.

Animals↗

Evidence for clostridial implication in necrotizing enterocolitis through bacterial fermentation in a gnotobiotic quail model.

Despite extensive research, the pathogenesis of neonatal necrotizing enterocolitis (NEC) remains elusive. The aim of our work was to investigate the role of bacterial strains involved in NEC in gnotobiotic quails as experimental model. Six groups of germ-free quails that were fed a lactose diet were associated with Klebsiella pneumoniae, Clostridium perfringens, C. difficile, C. paraputrificum, or C. butyricum (two strains). Implantation level, incidence of cecal lesions, production of short-chain fatty acids, and histologic lesions of the cecal wall were investigated. Whatever the strain, the implantation level was high (10(9) UFC/g). Neither K. pneumoniae nor C. difficile induced any cecal lesions. In contrast, the four other clostridial strains led to cecal NEC-like lesions with a variable occurrence: four of 12 quails for C. perfringens, eight of 12 quails for C. paraputrificum, and the same highest value, nine of 12 quails and eight of 10 quails for both C. butyricum strains. Gross aspects of the lesions may be linked to the short-chain fatty acid profiles and/or concentrations: thickening of the cecal wall (C. butyricum and C. perfringens) with high proportion of butyric acid, hemorrhages (C. paraputrificum) with high proportion of iso-butyric acid, and presence of other iso-acids. In addition, C. butyricum was characterized by pneumatosis, linked to a high gas production. Microscopic aspects confirmed the presence of edemas and intramucosa hemorrhages. Clostridia species, whose role is controversial, seem to be strongly implicated in NEC through excessive production of butyric acid as a result of colonic lactose fermentation. These results call for anaerobe detection in feces of infants who have NEC.

Animals↗

[Epidemic outbreak of necrotizing enterocolitis coincident with an epidemic of neonatal rotavirus gastroenteritis].

Authors present four cases of neonatal necrotizing enterocolitis occurred during an outbreak of acute enteritis. From november 1985 to beginning of february 1986, forty-seven out of 588 newborn infants were involved. In 22 affected infants (46.8%) rotavirus were isolated from stools, whereas no bacterial or viral agent was recovered in 25 (53.2%). Four cases (8.6%) developed necrotizing enterocolitis.

Birth Weight↗