Ariel U. Spencer

Pediatric Short Bowel Syndrome: Redefining Predictors of Success

Objective:To determine predictors of survival and of weaning off parenteral nutrition (PN) in pediatric short bowel syndrome (SBS) patients. Summary Background Data:Pediatric SBS carries extensive morbidity and high mortality, but factors believed to predict survival or weaning from PN have been based on limited studies. This study reviews outcomes of a large number of SBS infants and identifies predictors of success. Methods:Multivariate Cox proportional hazards analysis was conducted on 80 pediatric SBS patients. Primary outcome was survival; secondary outcome was ability to wean off PN. Nonsignificant covariates were eliminated. P < 0.05 was considered significant. Results:Over a mean of 5.1 years of follow-up, survival was 58 of 80 (72.5%) and 51 weaned off PN (63.8%). Cholestasis (conjugated bilirubin ≥2.5 mg/dL) was the strongest predictor of mortality (relative risk [RR] 22.7, P = 0.005). Although absolute small bowel length was only slightly predictive, percentage of normal bowel length (for a given infants gestational age) was strongly predictive of mortality (if <10% of normal length, RR of death was 5.7, P = 0.003) and of weaning PN (if ≥10% of normal, RR of weaning PN was 11.8, P = 0.001). Presence of the ileocecal valve (ICV) also strongly predicted weaning PN (RR 3.9, P < 0.0005); however, ICV was not predictive of survival. Conclusions:Cholestasis and age-adjusted small bowel length are the major predictors of mortality in pediatric SBS. Age-adjusted small bowel length and ICV are the major predictors of weaning from PN. These data permit better prediction of outcomes of pediatric SBS, which may help to direct future management of these challenging patients.

Parenteral Nutrition–Associated Cholestasis in Neonates: Multivariate Analysis of the Potential Protective Effect of Taurine

BACKGROUND Neonates receiving parenteral nutrition (PN) are at risk for PN-associated cholestasis (PNAC); however, no preventive factors for PNAC have been clearly identified. Despite reports suggesting that taurine may prevent PNAC in neonates, such an effect of taurine has not yet been definitively demonstrated. We determined whether taurine supplementation reduces the incidence of PNAC in premature or critically ill neonates. METHODS This study was part of a prospective, randomized, multi-institutional trial designed to assess cholecystokinin vs placebo as a potential preventive therapy of PNAC. Taurine supplementation of PN varied between institutions. The presence or absence of taurine in PN was analyzed by multivariate analysis, with a primary outcome measure of serum conjugated bilirubin (CB) as a measure of PNAC. RESULTS Taurine reduced PNAC in premature infants (estimated maximum CB [95% confidence interval] 0.50 mg/dL [-0.17 to 1.18] for those receiving taurine, vs 3.45 mg/dL [1.79-5.11] for neonates not receiving taurine, approaching significance, p = .07). Taurine significantly reduced PNAC in infants with necrotizing enterocolitis (NEC; estimated maximum CB 4.04 mg/dL [2.85-5.23], NEC infants receiving taurine, vs 8.29 mg/dL [5.61-10.96], NEC infants not receiving taurine, p < .01). There were too few neonates with surgical anomalies to evaluate the effect of taurine in this group. CONCLUSIONS Within specific subgroups of neonatal patients, taurine supplementation does offer a very significant degree of protection against PNAC. Patients with NEC or severe prematurity are most likely to benefit substantially from taurine supplementation.

Outcomes in pediatric patients undergoing straight vs J pouch ileoanal anastomosis: a multicenter analysis

BACKGROUND Outcomes remain controversial for patients undergoing straight (SIAA) vs J pouch (JPAA) ileoanal anastomosis, particularly in children where fewer such cases are performed. Our 3 centers have had extensive experience with both techniques. Thus, we had the unique opportunity to compare outcomes within the same centers. METHODS We retrospectively analyzed 250 children after proctocolectomy with either SIAA or JPAA, for the first 3 years after pull-through. A functional stooling score was developed to further assess outcomes. Data were analyzed using chi(2) tests and generalized linear mixed models for repeated measures. RESULTS Two hundred three patients had sufficient data for complete analysis (42% males; mean surgery age, 15 +/- 7years). Surgical indications were ulcerative colitis (168) and familial adenomatoid polyposis (35). Surgical procedures included SIAA (112) and JPAA (91). Daytime and nighttime stooling frequencies were significantly higher (P < .013) for SIAA patients at 1 to 24 months after pull-through; however, stooling frequencies began approximating each other by this time. Symptomatic pouchitis (compared to enteritis after SIAA) was significantly higher in JPAA patients (odds ratio, 4.5; confidence interval, 2.32-8.72). Frequency of pouchitis declined with time. There was no significant difference in the incidence of surgical complications between the 2 groups. Finally, continence rates were strikingly good in both groups compared to previously reported series. CONCLUSION Straight ileoanal anastomosis and JPAA are associated with considerable morbidity; SIAA has higher stool frequency and JPAA has increased pouchitis. Over time, we found that problems improved, and functional stooling scores became similar. JPAA had consistently lower stool frequency and better continence rates; however, these differences were small and may have minimal clinical significance. In addition, such differences need to be balanced against the high rate of pouchitis with JPAA. Continence was excellent regardless of the technique.

Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition.

Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor α (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

IMPACT OF CALORIC INTAKE ON PARENTERAL NUTRITION-ASSOCIATED INTESTINAL MORPHOLOGY AND MUCOSAL BARRIER FUNCTION

BACKGROUND Parenteral nutrition (PN) is known to induce villus atrophy, epithelial cell (EC) apoptosis, and increase mucosal permeability. The study hypothesized that increasing amounts of energy delivery to mice would result in the best outcome, with the least effects on the mucosa. METHODS Mice were randomized to enteral controls (saline infusion with ad libitum enteral food) or to 1 of 3 PN groups (with no enteral nutrition): full (100% of daily average energy intake for the mouse), reduced (75% of energy intake) or very low (50% of energy intake). Mice received PN for 7 days. Mucosal morphology, EC apoptosis, and bacterial translocation were assessed. RESULTS Villus height decreased significantly with decreasing levels of caloric intake and was significantly lower in all PN groups compared with controls. Body weight loss was significantly greater in PN groups vs controls and was greatest in mice with the lowest caloric delivery. A consistent trend toward a higher EC apoptotic index with decreasing caloric intake was observed, and apoptosis in all PN groups exceeded controls (2-fold). All PN groups demonstrated greater bacterial translocation than controls. CONCLUSIONS PN induces intestinal EC apoptosis and villus and crypt atrophy, even at 100% of predicted energy needs, and such changes increased with greater reduction of energy intake. This study supports a concept that lack of enteral nutrition, rather than absolute caloric levels, is responsible for many of the adverse effects of PN. The study also allows the investigators to better optimize a mouse model of PN delivery.

Mechanical extension implants for short bowel syndrome

Short-bowel syndrome (SBS) is a rare, potentially lethal medical condition where the small intestine is far shorter than required for proper nutrient absorption. Current treatment, including nutritional, hormone-based, and surgical modification, have limited success resulting in 30% to 50% mortality rates. Recent advances in mechanotransduction, stressing the bowel to induce growth, show great promise; but for successful clinical use, more sophisticated devices that can be implanted are required. This paper presents two novel devices that are capable of the long-term gentle stressing. A prototype of each device was designed to fit inside a short section of bowel and slowly extend, allowing the bowel section to grow approximately double its initial length. The first device achieves this through a dual concentric hydraulic piston that generated almost 2-fold growth of a pig small intestine. For a fully implantable extender, a second device was developed based upon a shape memory alloy actuated linear ratchet. The proof-of-concept prototype demonstrated significant force generation and almost double extension when tested on the benchtop and inside an ex-vivo section of pig bowel. This work provides the first steps in the development of an implantable extender for treatment of SBS.

INTESTINAL INTRAEPITHELIAL LYMPHOCYTE DERIVED ANGIOTENSIN CONVERTING ENZYME MODULATES EPITHELIAL CELL APOPTOSIS

Background & Aims: Intestinal adaptation in short bowel syndrome (SBS) consists of increased epithelial cell (EC) proliferation as well as apoptosis. Previous microarray analyses of intraepithelial lymphocytes (IEL) gene expression after SBS showed an increased expression of angiotensin converting enzyme (ACE). Because ACE has been shown to promote alveolar EC apoptosis, we examined if IEL-derived ACE plays a role in intestinal EC apoptosis.Methods: Mice underwent either a 70% mid-intestinal resection (SBS group) or a transection (Sham group) and were studied at 7 days. ACE expression was measured, and ACE inhibition (ACE-I, enalaprilat) was used to assess ACE function.Results: IEL-derived ACE was significantly elevated in SBS mice. The addition of an ACE-I to SBS mice resulted in a significant decline in EC apoptosis. To address a possible mechanism, tumor necrosis factor alpha (TNF-α) mRNA expression was measured. TNF-α was significantly increased in SBS mice, and decreased with ACE-I. Interestingly, ACE-I was not able to decrease EC apoptosis in TNF-α knockout mice.Conclusions: This study shows a previously undescribed expression of ACE by IEL. SBS was associated with an increase in IEL-derived ACE. ACE appears to be associated with an up-regulation of intestinal EC apoptosis. ACE-I significantly decreased EC apoptosis.

Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme

Angiotensin converting enzyme (ACE) has been shown to be involved in regulation of apoptosis in nonintestinal tissues. This study examined the role of ACE in the modulation of intestinal adaptation utilizing ACE knockout mice (ACE-/-). A 60% small bowel resection (SBR) was used, since this model results in a significant increase in intestinal epithelial cell (EC) apoptosis as well as proliferation. Baseline villus height, crypt depth, and intestinal EC proliferation were higher, and EC apoptosis rates were lower in ACE-/- compared with ACE+/+ mice. After SBR, EC apoptosis rates remained significantly lower in ACE-/- compared with ACE+/+ mice. Furthermore, villus height and crypt depth after SBR continued to be higher in ACE-/- mice. The finding of a lower bax-to-bcl-2 protein ratio in ACE-/- mice may account for reduced EC apoptotic rates after SBR in ACE-/- compared with ACE+/+ mice. The baseline higher rate of EC proliferation in ACE-/- compared with ACE+/+ mice may be due to an increase in the expression of several EC growth factor receptors. In conclusion, ACE appears to have an important role in the modulation of intestinal EC apoptosis and proliferation and suggests that the presence of ACE in the intestinal epithelium has a critical role in guiding epithelial cell adaptive response.