Eric A. Sparks

Serious Congenital Heart Disease and Necrotizing Enterocolitis in Very Low Birth Weight Neonates

BACKGROUND Infants with serious congenital heart disease (CHD) appear to be at increased risk for necrotizing enterocolitis (NEC). This study aimed to quantify the incidence and mortality of NEC among very low birth weight (VLBW) neonates with serious CHD, and identify specific CHD diagnoses at the highest risk for developing NEC. STUDY DESIGN Data were prospectively collected on 257,794 VLBW (401 to 1,500 g) neonates born from 2006 to 2011 and admitted to 674 Vermont Oxford Network US centers. Entries were coded for specific CHD diagnoses and reviewed for completeness and consistency. Survival was defined as alive in-hospital at 1 year or discharge. RESULTS Of eligible neonates, 1,931 had serious CHD. Of these, 253 (13%) developed NEC (vs 9% in infants without CHD, adjusted odds ratio [AOR] 1.80, p<0.0001). Mortality for neonates with CHD and no NEC was 34%, vs 55% for those with CHD and NEC (p<0.0001). Both groups of CHD patients had higher mortality than infants with NEC without CHD (28%, p<0.0001). Although NEC mortality overall decreases with higher birth weight, mortality for NEC and CHD together does not. CONCLUSIONS The incidence of NEC is significantly higher in VLBW neonates when CHD is present. The mortality of CHD and NEC together is substantially higher than that with each disease alone. Infants with atrioventricular canal appear to have higher risk for developing NEC than other CHD diagnoses. In addition to providing benchmark incidence and mortality data, these findings may have utility in the further study of the pathophysiology of NEC.

Necrotizing enterocolitis is associated with earlier achievement of enteral autonomy in children with short bowel syndrome.

PURPOSE Necrotizing enterocolitis (NEC) remains one of the most common underlying diagnoses of short bowel syndrome (SBS) in children. The relationship between the etiology of SBS and ultimate enteral autonomy has not been well studied. This investigation sought to evaluate the rate of achievement of enteral autonomy in SBS patients with and without NEC. METHODS Following IRB approval, 109 patients (2002-2014) at a multidisciplinary intestinal rehabilitation program were reviewed. The primary outcome evaluated was achievement of enteral autonomy (i.e. fully weaning from parenteral nutrition). Patient demographics, primary diagnosis, residual small bowel length, percent expected small bowel length, median serum citrulline level, number of abdominal operations, status of the ileocecal valve (ICV), presence of ileostomy, liver function tests, and treatment for bacterial overgrowth were recorded for each patient. RESULTS Median age at PN onset was 0 weeks [IQR 0-0]. Median residual small bowel length was 33.5 cm [IQR 20-70]. NEC was present in 37 of 109 (33.9%) of patients. 45 patients (41%) achieved enteral autonomy after a median PN duration of 15.3 [IQR 7.2-38.4]months. Overall, 64.9% of patients with NEC achieved enteral autonomy compared to 29.2% of patients with a different primary diagnosis (p=0.001, Fig. 1). Patients with NEC remained more likely than those without NEC to achieve enteral autonomy after two (45.5% vs. 12.0%) and four (35.7% vs. 6.3%) years on PN (Fig. 1). Logistic regression analysis demonstrated the following parameters as independent predictors of enteral autonomy: diagnosis of NEC (p<0.002), median serum citrulline level (p<0.02), absence of a jejunostomy or ileostomy (p=0.013), and percent expected small bowel length (p=0.005). CONCLUSIONS Children with SBS because of NEC have a significantly higher likelihood of fully weaning from parenteral nutrition compared to children with other causes of SBS. Additionally, patients with NEC may attain enteral autonomy even after long durations of parenteral support.

Extraluminal distraction enterogenesis using shape-memory polymer

PURPOSE Although a few techniques for lengthening intestine by mechanical stretch have been described, they are relatively complex, and the majority involve placement of an intraluminal device. Ideally, techniques applicable to humans would be easy to perform and extraluminal to avoid the potential for mucosal injury. This study of distraction enterogenesis used an extraluminal, radially self-expanding shape-memory polymer cylinder and a simple operative approach to both elongate intestine and grow new tissue. METHODS Young Sprague Dawley rats (250-350 g) underwent Roux-en-Y isolation of a small intestinal limb and were divided in three groups: no further manipulation (Control 1, C1); placement of a nonexpanding device (Control 2, C2); or placement of a radially expanding device by the limb (Experimental, Exp). For C2 and Exp animals, the blind end of the limb was wrapped around the radially expanding cylindrical device with the limb-end sutured back to the limb-side. Bowel length was measured at operation and at necropsy (14 days) both in-situ and ex-vivo under standard tension (6g weight). Change in length is shown as mean ± standard deviation. A blinded gastrointestinal pathologist reviewed histology and recorded multiple measures of intestinal adaptation. The DNA to protein ratio was quantified as a surrogate for cellular proliferation. Changes in length, histologic measures, and DNA:protein were compared using analysis of variance, with significance set at P<0.05. RESULTS The length of the Roux limb in situ increased significantly in Exp animals (n=8, 29.0 ± 5.8mm) compared with C1 animals (n=5, -11.2 ± 9.0mm, P<0.01). The length of the Roux limb ex vivo under standard tension increased in the Exp group (25.8 ± 4.2mm) compared with the C2 group (n=6, -4.3 ± 6.0, P<0.01). There were no differences in histologic measures of bowel adaptation between the groups, namely villous height and width, crypt depth, crypt density, and crypt fission rate (all P ≥ 0.08). Muscularis mucosal thickness was also not different (P=0.25). There was no difference in DNA:protein between groups (P=0.47). CONCLUSION An extraluminally placed, radially expanding shape-memory polymer cylinder successfully lengthened intestine, without damaging mucosa. Lack of difference in muscularis thickness and a constant DNA:protein ratio suggests that this process may be related to actual growth rather than mere stretch. This study demonstrated a simple approach that warrants further study aiming at potential clinical applicability.

Preservation of Biochemical Liver Function With Low-Dose Soy-Based Lipids in Children with Intestinal Failure Associated Liver Disease

Objectives: Intestinal failure–associated liver disease (IFALD) contributes to significant morbidity in pediatric patients with intestinal failure (IF); however, the use of parenteral nutrition (PN) with a fish oil–based intravenous (IV) emulsion (FO) has been associated with biochemical reversal of cholestasis and improved outcomes. Unfortunately, FO increases the complexity of care: because it can be administered only under Food and Drug Administration compassionate use protocols requiring special monitoring, it is not available as a 3-in-1 solution and is more expensive than comparable soy-based IV lipid emulsion (SO). Because of these pragmatic constraints, a series of patient families were switched to low-dose (1 g kg−1 day−1) SO following biochemical resolution of cholestasis. The present study examines whether reversal of cholestasis and somatic growth are maintained following this transition. Methods: The present study is a chart review of all children with IFALD who switched from FO to SO following resolution of cholestasis. Variables are presented as medians (interquartile ranges). Comparisons were performed using the Wilcoxon signed-rank test. Results: Seven patients ages 25.9 (16.2–43.2) months were transitioned to SO following reversal of cholestasis using FO. At a median follow-up of 13.9 (4.3–50.1) months, there were no significant differences between pretransition and post-transition serum alanine and aspartate aminotransferases, direct bilirubin, and weight-for-age z scores. Because of recurrence of cholestasis, 1 patient was restarted on FO after 4 months on SO. Conclusions: Biochemical reversal of IFALD and growth were preserved after transition from FO to SO in 6 of 7 (86%) patients. Given the challenges associated with the use of FO, SO may be a viable alternative in select patients with home PN.

Contemporary Outcomes of Infants with Gastroschisis in North America: A Multicenter Cohort Study

Objective To quantify outcomes and analyze factors predictive of morbidity and mortality in infants with gastroschisis. Study design Clinical data regarding neonates with gastroschisis born between 2009 and 2014 were prospectively collected at 175 North American centers. Multivariate regression was used to assess risk factors for mortality and length of stay (LOS). Results Gastroschisis was diagnosed in 4420 neonates with median birth weight 2410 g (IQR 2105–2747). Survival (discharge home or alive in hospital at 1 year) was 97.8% with a 37 day median LOS (IQR 27–59). Sepsis, defined by positive blood or cerebrospinal fluid culture, was the only significant independent predictor of mortality (P = .04). Significant independent determinants of LOS and the percentage of neonates affected were as follows: bowel resection (9.8%, P < .0001), sepsis (8.6%, P < .0001), presence of other congenital anomalies (7.6%, including 5.8% with intestinal atresias, P < .0001), necrotizing enterocolitis (4.5%, P < .0001), and small for gestational age (37.3%, P = .0006). Abdominal surgery in addition to gastroschisis repair occurred in 22.3%, with 6.4% receiving gastrostomy or jejunostomy tubes and 6.3% requiring ostomy creation. At discharge, 57.0% were less than the 10th percentile weight for age. The mode of delivery (52.4% cesarean delivery) was not associated with any differences in outcome. Conclusions Although neonates with gastroschisis have excellent overall survival they remain at risk for death from sepsis, prolonged hospitalization, multiple abdominal operations, and malnutrition at discharge. Outcomes appear unaffected by the use of cesarean delivery. Further opportunities for quality improvement include sepsis prevention and enhanced nutritional support.

Enteral autonomy, cirrhosis, and long term transplant-free survival in pediatric intestinal failure patients.

PURPOSE Patient selection for transplant evaluation in pediatric intestinal failure is predicated on the ability to assess long-term transplant-free survival. In light of trends toward improved survival of intestinal failure patients in recent decades, we sought to determine if the presence of biopsy-proven hepatic cirrhosis or the eventual achievement of enteral autonomy were associated with transplant-free survival. METHODS After IRB approval, records of all pediatric intestinal failure patients (parenteral nutrition (PN) >90 days) treated at a single intestinal failure center from February 2002 to September 2014 were reviewed. Chi-squared, Mann-Whitney, and log-rank testing were performed as appropriate. RESULTS Of 313 patients, 174 eventually weaned off PN. Liver biopsies were available in 126 patients (most common indication was intestinal failure associated liver disease, IFALD), and 23 met histologic criteria for cirrhosis. Transplant-free survival for the whole cohort of 313 patients was 94.7% at 1 year and 89.2% at 5 years. Among patients with liver biopsies, transplant-free survival in cirrhotics vs. noncirrhotics was 95.5% vs. 94.1% at one year and 95.5% vs. 86.7% at 5 years (P=0.29). Transplant-free survival in patients who achieved enteral autonomy compared with patients who remained PN dependent was 98.2% vs. 90.3% at one year and 98.2% vs. 76.9% at 5 years (P<0.001). There was no association between cirrhosis and eventual enteral autonomy (P=0.88). CONCLUSIONS Achieving enteral autonomy was associated with improved transplant-free survival in pediatric intestinal failure patients. There was no association between histopathological diagnosis of cirrhosis and transplant-free survival in the cohort. These data suggest that automatic transplant referral may not be required for histopathological diagnosis of cirrhosis alone, and that ongoing efforts aimed at achievement of enteral autonomy remain paramount in pediatric intestinal failure.

Metabolic bone disease in pediatric intestinal failure patients: Prevalence and risk factors ☆ ☆☆

PURPOSE Patients with intestinal failure (IF) are known to have impaired absorption of nutrients required for maintenance of skeletal mass. Rates and risk factors of low bone mineral density (BMD) are unknown in pediatric IF patients. METHODS Following IRB approval, patients with IF having undergone DXA scans were identified and laboratory, clinical, and nutritional intake variables were recorded. Low BMD was defined by a z-score of less than or equal to -2.0. Univariate followed by multivariable regression analysis was performed. RESULTS Sixty-five patients underwent a total of 99 routine DXA scans. Twenty-seven (41%) had vitamin D deficiency, 22 (34%) had low BMD, and nineteen (29%) had a history of fractures. Variables noted to be associated with low BMD (p<0.1) on univariate analysis were considered for multivariable regression. Multivariable regression identified WAZ and serum calcium levels (p<0.05) as independent predictors of low BMD z-score. None of the other evaluated factors were associated with the risk of low BMD. Low BMD was not associated with risk of fractures. CONCLUSION There is a significant incidence of low BMD in children with IF. WAZ and lower serum calcium levels are associated with risk of low BMD. Additional long term prospective studies are needed to further characterize the risk factors associated with low BMD.

Operative indications in recurrent ileocolic intussusception

BACKGROUND Air-contrast enema (ACE) is standard treatment for primary ileocolic intussusception. Management of recurrences is less clear. This study aimed to delineate appropriate therapy by quantifying the relationship between recurrence and need for bowel resection, pathologic lead points (PLP), and complication rates. METHODS After IRB approval, a single institution review of patients with ileocolic intussusception from 1997 to 2013 was performed, noting recurrences, outcomes, and complications. Fishers exact and t-tests were used. RESULTS Of 716 intussusceptions, 666 were ileocecal. Forty-four underwent bowel resection, with 29 PLPs and 9 ischemia/perforation. Recurrence after ACE occurred in 96 (14%). Recurrence did not predict PLP (P=0.25). Recurrence (≥3) was associated with higher resection rate (P=0.03), but not ischemia/perforation (P=0.75). ACE-related complications occurred in 4 (0.5%) patients. Successful initial ACE had 98% negative predictive value for resection and PLP (e.g., after successful ACE, 2% had resections, 2% PLP). After failed initial ACE, 36% received resection, and 23% had PLP (P<0.001). CONCLUSIONS Recurrence is associated with a greater risk of resection but not PLP or ACE-complication. Failed ACE is associated with increased risk for harboring PLP and receiving resection. ACE should be the standard treatment in recurrent intussusception, regardless of number of recurrences.

Factors Affecting Spontaneous Closure of Gastrocutaneous Fistulae After Removal of Gastrostomy Tubes in Children With Intestinal Failure.

BACKGROUND Children with intestinal failure (IF) frequently require gastrostomy tubes (GTs) for long-term nutrition support. Risk factors for persistent gastrocutaneous fistulae (GCFs) in pediatric patients with IF are largely unknown but may include underlying nutrition status and duration of indwelling GT. MATERIALS AND METHODS Records of patients with IF having undergone GT removal and allowed a trial at spontaneous closure were reviewed. Nonparametric continuous variables were analyzed using the Wilcoxon rank sum test. Post hoc analysis was performed to identify the optimal threshold of GT duration predicting probability of spontaneous closure identified using receiver operating characteristic curve analysis. RESULTS Fifty-nine children with IF undergoing GT removal were identified. Spontaneous closure occurred in 36 (61%) sites, while 23 (39%) underwent operative closure at a median 67 days after GT removal. The duration of indwelling GT was significantly shorter in the spontaneous closure group (11.5 vs 21 months, P = .002). Of 33 GT indwelling for ≤ 18 months, 28 (85%) closed spontaneously, compared with only 9 of 26 (35%) with duration >18 months (P < .001). With GCF persisting beyond 7 days, only 21% (6/28) of sites closed spontaneously, but this dropped to 6% (1/18) of cases with concurrent GT duration >18 months. CONCLUSIONS Of the risk factors evaluated, only prolonged GT duration was associated with an increased likelihood of failure to close spontaneously. It is significantly less likely in pediatric patients with IF in whom GCF persists >7 days, particularly if the duration of GT is >18 months. Relatively earlier operative closure should be considered in this group.

Hospital transfers and patterns of mortality in very low birth weight neonates with surgical necrotizing enterocolitis

PURPOSE The objectives of this study were to evaluate mortality rates in very low birth weight (VLBW) infants with surgical necrotizing enterocolitis (NEC) by level of available surgical resources and to determine the effect of hospital transfer on mortality. METHODS Mortality among 4328 VLBW neonates with surgical NEC born 2009-2013 was assessed using the Vermont Oxford Network database. NICUs were classified by availability of resources as a marker of overall center capability: type A (restrictions on ventilation or do not routinely perform major neonatal surgery), type B (perform major neonatal surgery but not cardiac bypass), and type C (perform major surgery, including cardiac bypass in infants). RESULTS Mortality was higher among those who had surgery at type B centers versus type C centers (44.3% vs 36.4%, adjusted prevalence ratio 1.20 (95% CI: 1.08, 1.33)). Neonates who were not transferred between birth and surgery had a higher mortality compared to those transferred (44.6% vs 31.6%, adjusted prevalence ratio 1.39 (95% CI: 1.25, 1.55)). CONCLUSION Transfer between birth and surgery and a higher level of surgical resources at the operative center were associated with lower mortality. Early transfer of high risk neonates to centers with higher levels of surgical resources may be warranted.