Phillip V. Gordon

Necrotizing Enterocolitis Among Neonates in the United States

BACKGROUND: Prior studies have identified individual risk factors that are associated with necrotizing enterocolitis (NEC); however, the small sample sizes of these previous studies have not allowed the analysis of potential interaction between multiple variables and NEC. Our purpose was to describe the incidence and risk factors for NEC in premature neonates admitted for intensive care.METHODS: We identified neonates as having NEC if they met accepted diagnostic criterion for necrotizing enterocolitis. Using a national database, we assessed the association between NEC and a battery of risk factors previously reported in peer-reviewed literature.RESULTS: There were 15,072 neonates that met inclusion criteria; 14,682 did not have NEC, while 390 (2.6%) met criterion for NEC. Multivariate analysis showed that low birth weight was the most important risk factor for NEC. Other factors that were associated with an increased risk of NEC were exposure to antenatal glucocorticoids, vaginal delivery, need for mechanical ventilator support, exposure to both glucocorticoids and indomethacin during the first week of life, absence of an umbilical arterial catheter, and low Apgar score at 5 minutes. Length of hospital stay and mortality were higher in neonates with NEC than in neonates without NEC.CONCLUSIONS: NEC remains an important cause of morbidity and mortality in prematurely born neonates. In contrast to previous studies, we found that exposure to antenatal glucocorticoids was associated with an increased risk for NEC independent of birth weight.

Emerging trends in acquired neonatal intestinal disease: is it time to abandon Bell's criteria?

In the last decade, it has become increasingly clear that necrotizing enterocolitis (NEC) is neither a uniform nor a well-defined disease entity. There are many factors that are forcing this unwelcome realization upon the neonatal and pediatric surgery communities. In the course of this manuscript we will review the history and the physical findings of the disparate etiologies of acquired neonatal intestinal diseases (ANIDs), some which do lead to the common final pathology of NEC and some which do not. New guidelines for distinguishing between ANIDs will also be suggested.

New insights into spontaneous intestinal perforation using a national data set: (1) SIP is associated with early indomethacin exposure

Background:Spontaneous intestinal perforation (SIP) is increasingly common in the premature infant and is associated with significant morbidity. Indomethacin use has been implicated as a co-risk factor for SIP when combined with glucocorticoids, but previous evidence argued against indomethacin being an independent risk factor when used prophylactically.Objectives:(1) To establish a homogeneous cohort of SIP patients in a national data set and to contrast them to patients with surgical necrotizing enterocolitis (NEC). (2) To test the hypothesis that early post-natal indomethacin is independently associated with SIP.Methods:A large de-identified data set was retrospectively queried by diagnosis, and then multiple antenatal and post-natal variables were tested by both univariate and multivariate analysis to identify associations with SIP. Sub-analyses were also performed to look at the timing of drug administration.Results:There were 2105 patients evaluated in the data set. Patients were divided into matched controls (n=581), those with SIP without report of NEC (n=633) and those with NEC requiring surgery (n=891). Infants with SIP were more likely to have a patent ductus arteriosus and more likely to be treated with vasopressors than either control or NEC patients. Compared to infants with NEC, patients with SIP were smaller, less mature and required more support. SIP was also diagnosed earlier than NEC (median of 7 vs 15 days). Patients with SIP were more likely to be treated with indomethacin, hydrocortisone or both on days of life 0–3 than controls.Conclusions:(1) Surgical NEC and SIP have significant differences in presentation, demographics and morbidity. (2) A detailed look at drug timing revealed that early post-natal indomethacin is independently associated with SIP.

A Randomized-Controlled Trial of Prophylactic Hydrocortisone Supplementation for the Prevention of Hypotension in Extremely Low Birth Weight Infants

OBJECTIVE:Extremely low birth weight (ELBW) infants are at risk for hypotension. Abnormal adrenal function may play a role in the pathogenesis of hypotension, and therefore, the administration of hydrocortisone (HC) may be an effective treatment for hypotension in some infants. However, the efficacy of prophylactic HC to prevent the use of vasopressors for a defined hypotensive state has not been studied. We conducted a randomized-controlled trial to determine the potential role on adrenal insufficiency in early neonatal hypotension and to determine the effectiveness of prophylactic HC in reducing treatment of hypotension in ELBW infants.STUDY DESIGN:Infants were assigned to receive either HC or placebo within the first 3 hours of life. Therapy was continued for 5 days. The presence of hypotension was based on an operational definition and treatment with vasopressors (VP) was standardized based on an a priori protocol.RESULTS:A total of 34 patients were enrolled. Baseline characteristics were similar between groups. Of the HC group 25% received VP at 24 hours of age compared to 44% of the placebo group. On day of life 2, only 7% of the HC group received VP compared to 39% of the placebo group (p<0.05).CONCLUSION:Prophylactic treatment with HC reduces the incidence of hypotension, defined by treatment with VP, among ELBW infants during the first 2 days of life. However, the mounting evidence that prophylactic administration of glucocorticoids in the first days of life is harmful to ELBW infants makes HC prophylaxis unwise until the efficacy of treatment relative to safety can be clearly established.

New insights into spontaneous intestinal perforation using a national data set: (2) two populations of patients with perforations

Background:Spontaneous intestinal perforation (SIP) is increasingly common in the premature infant and has been demonstrated to be associated with early postnatal administration of glucocorticoids and indomethacin. Before survival of the extremely low birth weight (ELBW) infant, SIP was thought to be a rare, congenitally acquired disease sporadically affecting the muscularis of the distal intestine. These disparate views of etiology have not been previously reconciled in the literature.Objectives:(1) To establish a cohort of SIP patients in a national data set. (2) To use timing of diagnosis as a unique data element and thereby differentiate between SIP cases which are susceptible to postnatal risk factors versus those occurring at or immediately after birth (and therefore not exposed to postnatal risk factors).Methods:A large deidentified national data set was used to retrospectively look at timing of diagnosis and then the cohort was divided into postnatal treatment groups for further subanalyses. This analysis resulted in the division of the cohort into early and late diagnosis SIP subcohorts. These were then queried retrospectively by univariate analysis to look for differences in demographics between the two (using a P-value < 0.05)Results:There were 633 patients with SIP evaluated in this data set. The early SIP cohort (0–3 days) was made up of 116 infants with a median BW of 1.401 kg, whereas the late cohort (4–14 days) held 386 infants with a median BW of 775 g. Infants with early SIP were significantly more likely to: be male, have higher Apgar scores, have not received antenatal steroids, surfactant or required mechanical ventilation.Conclusions:Two populations of infants acquire SIP: ELBW infants acquire SIP on average between 7 and 10 days of life after exposure to indomethacin and glucocorticoids (either endogenous or exogenous), and infants with early SIP (0–3 days) who are significantly less likely to have been exposed to postnatal risk factors and are less premature.

Understanding Clinical Literature Relevant to Spontaneous Intestinal Perforations

Spontaneous intestinal perforation (SIP) has emerged as a disease of extremely low-birth-weight (ELBW) infants over the last two decades. Several risk factors have been associated with this disease including early postnatal steroids (EPS; use within the first week of life), early use of indomethacin (EUI; use within the first 3 postnatal days), and the synergistic combination of the two. These two risk factors are thought to play a causal role in the etiology of SIP through their effects on ileal trophism and motility. Two infectious agents ( Candida and Staphylococcus epidermidis) are commonly grown from peritoneal cultures of patients with SIP. It is less clear whether these infections play a causal role or if they represent comorbidities of perforation. Chorioamnionitis is thought to be a risk factor for SIP, as is the stress and elevated cortisol that accompanies it. Recent analyses suggest that antenatal indomethacin may also be a risk factor for SIP, particularly when given close to birth. These latter variables are more challenging to rank in importance compared with EPS and EUI, which have been repeatedly associated with SIP in both retrospective cohorts and randomized controlled trials. Because neonatal care of the ELBW infant is commonly standardized, the habitual combination of any of these risk factors potentially amplifies the risk of SIP. Many of these factors are medicines, thus SIP risk is exacerbated by select forms of polypharmacy. Our challenge lies in understanding how these drug interactions lead to harm.

New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with spontaneous intestinal perforation.

Objective:To examine whether antenatal steroids (ANS), alone or with early indomethacin, are associated with spontaneous intestinal perforation (SIP). SIP is a known complication of concurrent post-natal administration of glucocorticoid and indomethacin in extremely low birth weight (ELBW) infants.Study design:A large de-identified national data set was retrospectively examined for infants with SIP without any report of other malformation or necrotizing entrocolitis. A control group was then derived matching for gender and birth weight (±20 g). Pre- and post-natal variables were tested by both univariate and multivariate analysis to identify associations with SIP.Results:From January 1996 to June 2004, there were 2 27 711 discharges from Pediatrix neonatal intensive care unit sites. From this population 388 infants with SIP associated with ELBW were compared to matched controls. Infants with SIP were more likely to have received early indomethacin and to have received a combination of early indomethacin with post-natal glucocorticoids (P<0.05 for both). When used alone (without subsequent indomethacin), ANS showed no association with SIP. When used in conjunction with indomethacin, ANS did not increase the rate of SIP beyond indomethacin alone.Conclusion:ELBW Infants that acquire SIP were more likely to have been exposed to early indomethacin and post-natal glucocorticoids. However, no association was found between SIP and ANS within a well-powered cohort.

Can a national dataset generate a nomogram for necrotizing enterocolitis onset

Objective:Mother’s own milk and donor human milk use is increasing as a means of necrotizing enterocolitis (NEC) prevention. Early onset of enteral feeding has been associated with improvement of many outcomes but has not been shown to reduce the incidence of NEC. Better definition of the window of risk for NEC by gestational strata should improve resource management with respect to donor human milk and enhance our understanding of NEC timing and pathogenesis. Our objective was to establish a NEC dataset of sufficient size and quality, then build a generalizable model of NEC onset from the dataset across gestational strata.Study Design:We used de-identified data from the Pediatrix national dataset and filtered out all diagnostic confounders that could be identified by either specific diagnoses or logical exclusions (example dual diagnoses), with a specific focus on NEC and spontaneous intestinal perforation (SIP) as the outcomes of interest. The median day of onset was plotted against the gestational age for each of these diagnoses and analyzed for similarities and differences in the day of diagnosis.Result:Onset time of medical NEC was inversely proportional to gestation in a linear relationship across all gestational ages. We found the medical NEC dataset displayed characteristics most consistent with a homogeneous disease entity, whereas there was a skew towards early presentation in the youngest gestation groups of surgical NEC (suggesting probable SIP contamination).Conclusion:Our national dataset demonstrates that NEC onset occurs in an inverse stereotypic, linear relationship with gestational age at birth. Medical NEC is the most reliable sub-cohort for the purpose of determining the temporal window of NEC risk.

A neonatal mouse model of intestinal perforation : Investigating the harmful synergism between glucocorticoids and indomethacin

Background: Early postnatal steroids and indomethacin in combination have been shown to increase the risk of spontaneous intestinal perforation (SIP) in infants with extremely low birth weight (ELBW), but the mechanism behind this synergistic effect is unknown. Materials and Methods: Based on literature in a variety of models suggesting that glucocorticoids and nonsteroidal antiinflammatory agents diminish complementary isoforms of nitric oxide synthase (NOS), we hypothesized that perturbations in NO metabolism contribute to SIP. Results: Our results using newborn wild-type (WT) and endothelial NOS-knockout (eNOS KO) mice treated with dexamethasone and/or indomethacin indicate that indomethacin treatment diminishes ileal eNOS abundance; dexamethasone treatment diminishes ileal inducible NOS and neuronal NOS (nNOS); 100% of dexamethasone-treated eNOS KO mice die after 3 days; eNOS KO mice treated for 2 days with dexamethasone develop acute pyloric stenosis in association with reduced expression of pyloric nNOS; and isolated ileum from eNOS KO mice treated for 2 days with dexamethasone exhibit a significant decrease in spontaneous peristalsis, decreased circumference, and decreased capacitance for forced volume before ileal perforation compared with ileum from untreated controls. Conclusions: Our findings suggest that eNOS and nNOS display functional overlap in the newborn mouse gastrointestinal tract and that simultaneous reduction in the activity of both NOS isoforms may be a risk factor for neonatal ileal perforation. If this holds true in human infants, then it provides a plausible etiologic explanation for the strong temporal association between SIP and the simultaneous treatment of ELBW infants with glucocorticoids and indomethacin.

Dexamethasone changes the composition of insulin-like growth factor binding proteins in the newborn mouse ileum.

Background Early postnatal glucocorticoid exposure accelerates the maturation of the bowel mucosa but results in bowel wall thinning in the newborn mouse ileum and increases the risk of focal ileal perforation in extremely premature infants. We have previously demonstrated a redistribution of insulin-like growth factor-I (IGF-I) from the submucosa in control animals to the distal villi of those treated with early postnatal dexamethasone, implicating IGF-I as an important mediator of dexamethasones capacity to alter tissue growth. To investigate the possibility that IGF binding proteins (IGFBPs) might contribute to this process, we characterized the localization and abundance of IGFBP peptides and mRNAs in the same model. Methods Newborn mice received daily intraperitoneal injections of dexamethasone (l &mgr;g/g) or phosphate-buffered saline and then were euthanized on day 3 of life. Their ileums were harvested and prepared for microscopy. Tissue sections of ileum from both treatment conditions were processed in parallel for immunolocalization of each of the six IGFBP peptides and for in situ hybridization of each of the six IGFBP transcripts. Results Transcripts for IGFBP-1, -2, and -3 were highly abundant and ubiquitous the ileal mucosa, whereas transcripts for IGFBP-4, -5, and -6 were less abundant in epithelial cells. There were no differences in abundance between control and dexamethasone-treated ileum with regard to mRNA localization or abundance for IGFBP-1, -2, -3, and -6. In contrast, mRNA transcripts for IGFBP-4 and -5 were modestly increased with dexamethasone treatment (although only IGFBP-4 was significant). Strikingly different patterns of IGFBP immunolocalization were observed between control and dexamethasone-treated animals. IGFBP-1, -2, -3, and -5 were not detected in control ileum, whereas IGFBP-4 and -6 were both present in the mucosa. In contrast, dexamethasone treatment resulted in dramatic mucosal increases in IGFBP-2, -3, -4, and -5, paralleling the changing distribution of IGF-I that we previously reported. Conclusion Taken together, these findings further implicate the IGF system as an important participant in dexamethasone-induced maturation in the newborn mouse ileum.