Martin L. Blakely

OBJECTIVES: Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months' corrected age. METHODS: Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. chi2, t test, and logistic regression analyses were used. RESULTS: A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.05-2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25-3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.17-2.73) compared with NoNEC. CONCLUSIONS: Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease.

Background: Perforated necrotizing enterocolitis is a major cause of morbidity and mortality in premature infants, and the optimal treatment is uncertain. We designed this multicenter randomized trial to compare outcomes of primary peritoneal drainage with laparotomy and bowel resection in preterm infants with perforated necrotizing enterocolitis.Methods: We randomly assigned 117 preterm infants (delivered before 34 weeks of gestation) with birth weights less than 1500 g and perforated necrotizing enterocolitis at 15 pediatric centers to undergo primary peritoneal drainage or laparotomy with bowel resection. Postoperative care was standardized. The primary outcome was survival at 90 days postoperatively. Secondary outcomes included dependence on parenteral nutrition 90 days postoperatively and length of hospital stay.Results: At 90 days postoperatively, 19 of 55 infants assigned to primary peritoneal drainage had died (34.5 percent), as compared with 22 of 62 infants assigned to laparotomy (35.5 percent, P=0.92). The percentages of infants who depended on total parenteral nutrition were 17 of 36 (47.2 percent) in the peritoneal-drainage group and 16 of 40 (40.0 percent) in the laparotomy group (P=0.53). The mean (+/-SD) length of hospitalization for the 76 infants who were alive 90 days after operation was similar in the primary peritoneal-drainage and laparotomy groups (126+/-58 days and 116+/-56 days, respectively; P=0.43). Subgroup analyses stratified according to the presence or absence of radiographic evidence of extensive necrotizing enterocolitis (pneumatosis intestinalis), gestational age of less than 25 weeks, and serum pH less than 7.30 at presentation showed no significant advantage of either treatment in any group.Conclusions: The type of operation performed for perforated necrotizing enterocolitis does not influence survival or other clinically important early outcomes in preterm infants. (ClinicalTrials.gov number, NCT00252681.).

OBJECTIVE: Purposes of this study were: 1) to compare mortality and postoperative morbidities (intra-abdominal abscess, wound dehiscence, and intestinal stricture) in extremely low birth weight (ELBW) infants who underwent initial laparotomy or drainage for necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP); 2) to determine the ability to distinguish NEC from IP preoperatively and the importance of this distinction on outcome measures; and 3) to evaluate the association between extent of intestinal disease determined at operation and outcome measures. BACKGROUND: ELBW infants who undergo operation for NEC or IP have a postoperative, in-hospital mortality rate of approximately 50%. Whether to perform laparotomy or drainage initially is controversial. Also unknown is the importance of distinguishing NEC from IP and the current ability to make this distinction based on objective data available prior to operation. METHODS: A prospective, multicenter cohort study of 156 ELBW infants at 16 neonatal intensive care units (NICU) within the NICHD Neonatal Research Network. RESULTS: Among the 156 enrolled infants, 80 underwent initial peritoneal drainage and 76 initial laparotomy. Mortality rate was 49% (76 of 156). Ninety-six patients had a preoperative diagnosis of NEC and 60 had presumed IP. There was a high level of agreement between the presumed preoperative diagnosis and intraoperative diagnosis in patients undergoing initial laparotomy (kappa = 0.85). The relative risk for death with a preoperative diagnosis of NEC (versus IP) was 1.4 (95% confidence interval, 0.99-2.1, P = 0.052). The overall incidence of postoperative intestinal stricture was 10.3%, wound dehiscence 4.4%, and intra-abdominal abscess 5.8%, and did not significantly differ between groups undergoing initial laparotomy versus initial drainage. CONCLUSIONS: Survival to hospital discharge after operation for NEC or IP in ELBW neonates remains poor (51%). Patients with a preoperative diagnosis of NEC have a relative risk for death of 1.4 compared with those with a preoperative diagnosis of IP. A distinction can be made preoperatively between NEC and IP based on abdominal radiographic findings and the patient's age at operation. Future randomized trials that compare laparotomy versus drainage would likely benefit from stratification of treatment assignment based on preoperative diagnosis.

Most studies of discordant xenograft rejection have focused on the roles of recipient xenoreactive antibody and complement as mediators of hyperacute rejection; there are essentially no data from in vivo studies as to the contribution of endothelial cell responses to the pathobiology of xenograft rejection. We hypothesized that the mechanism by which xenoreactive natural antibodies and complement of the recipient are involved in rejection of a discordant, immediately vascularized xenograft involves donor organ endothelial cell activation, with the consequences of such activation contributing significantly to the rejection process. We performed a kinetic analysis of rejection of guinea pig hearts by untreated Lewis rats or recipients depleted of complement activity that underwent delayed xenograft rejection. We report that in both hyperacute rejection and delayed xenograft rejection there is widespread evidence of endothelial cell activation, including expression of P-selectin and E-selectin, upregulation of tissue factor, and downregulation of thrombomodulin and antithrombin III expression. Many of these changes occur very early posttransplantation in grafts that are not completely rejected until approximately 3 days. In delayed xenograft rejection, an intense cellular infiltrate is seen that results from progressive accumulation of activated macrophages and natural killer cells. T cell receptor alpha/beta+T cells are present only at relatively low levels. This cellular infiltrate is associated with dense expression of pro-inflammatory cytokines, including interferon gamma, interleukin 1, and tumor necrosis factor-alpha. We conclude that both endothelial cell activation and infiltration by activated macrophages and natural killer cells may play an important role in xenograft rejection. These newly described features of the xenogeneic rejection response may require targeting by future therapeutic regimens aimed at prolonging xenograft survival.

Most studies of discordant xenograft rejection have focused on the roles of recipient xenoreactive antibody and complement as mediators of hyperacute rejection; there are essentially no data from in vivo studies as to the contribution of endothelial cell responses to the pathobiology of xenograft rejection. We hypothesized that the mechanism by which xenoreactive natural antibodies and complement of the recipient are involved in rejection of a discordant, immediately vascularized xenograft involves donor organ endothelial cell activation, with the consequences of such activation contributing significantly to the rejection process. We performed a kinetic analysis of rejection of guinea pig hearts by untreated Lewis rats or recipients depleted of complement activity that underwent delayed xenograft rejection. We report that in both hyperacute rejection and delayed xenograft rejection there is widespread evidence of endothelial cell activation, including expression of P-selectin and E-selectin, upregulation of tissue factor, and downregulation of thrombomodulin and antithrombin III expression. Many of these changes occur very early posttransplantation in grafts that are not completely rejected until approximately 3 days. In delayed xenograft rejection, an intense cellular infiltrate is seen that results from progressive accumulation of activated macrophages and natural killer cells. T cell receptor α/β+ T cells are present only at relatively low levels. This cellular infiltrate is associated with dense expression of pro-inflammatory cytokines, including interferon gamma, interleukin 1, and tumor necrosis factor-alpha. We conclude that both endothelial cell activation and infiltration by activated macrophages and natural killer cells may play an important role in xenograft rejection. These newly described features of the xenogeneic rejection response may require targeting by future therapeutic regimens aimed at prolonging xenograft survival.