Edward M. Barksdale

Current status of intestinal transplantation in children

PURPOSE A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). METHODS Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n=33), and multivisceral (MV) (n=8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis (n=14), volvulus (n=13), necrotizing enterocolitis (n=6), intestinal atresia (n=8), chronic intestinal pseudoobstruction (n=5), Hirschsprungs disease (n=4), microvillus inclusion disease (n=3), multiple polyposis (n=1), and trauma [n=1). RESULTS Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n=18), intestinal allograft rejection (n=52), posttransplant lymphoproliferative disease (n=16), cytomegalovirus (n=16) and graft-versus-host disease (n=4). A combination of associated complications included intestinal perforation (n=4), biliary leak (n=3), bile duct stenosis (n=1), intestinal leak (n=6), dehiscence with evisceration (n=4), hepatic artery thrombosis (n=3), bleeding (n=9), portal vein stenosis (n=1), intraabdominal abscess (n=11), and chylous ascites (n=4). Graft loss occurred as a result of rejection (n=8), infection (n=12), technical complications (n=8), and complications of TPN after graft removal (n=3). There were four retransplants (SB, n=1; LSB n=3). CONCLUSIONS Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation.

Management of intractable constipation with antegrade enemas in neurologically intact children.

Objectives To assess the benefit of antegrade enemas in children with severe constipation who were referred to a tertiary care center. Methods From 1997 to 1999, 12 children (9 male, aged 8.7 ± 4.4 years) underwent cecostomy placement. All children were neurologically normal and had been extensively examined to rule out organic causes of constipation. Follow-up included a questionnaire to interview caregivers 13.1 ± 8.5 months after cecostomy placement. Results For all children, antegrade enemas led to improvement in the number of bowel movements / week (7.1 versus 1.4, P < 0.005), number of soiling accidents / week (1.0 versus 4.7, P < 0.01), abdominal pain score (0.9 versus 2.9, P < 0.005), emotional health score (3.6 versus 1.9, P < 0.005), overall health score (3.6 versus 1.7, P < 0.005), number of medications used for constipation (0.8 versus 4.0, P < 0.005), number of missed school days / month (1.5 versus 7.5, P < 0.02), and number of physician office visits / year (9.2 versus 24.0, P < 0.05). Irrigation solutions used for the antegrade enemas included polyethylene glycol (67%), saline and glycerin solution (25%), and phosphate enema (8%), administered everyday in seven children and every other day in five children. Adverse events included skin breakdown and granulation tissue in one patient, leakage of irrigation solution in one patient, and dislodging of the tube in two patients. Five patients discontinued the use of antegrade enemas within a mean of 14.6 ± 9.1 months after beginning treatment. Conclusion Antegrade enemas through a cecostomy are a safe and satisfactory option for children who are neurologically intact and who have severe constipation that does not respond to medical treatment.

Internal anal sphincter achalasia in children: Clinical characteristics and treatment with Clostridium botulinum toxin

Objectives To describe the clinical characteristics of children with internal anal sphincter (IAS) achalasia and to evaluate the benefit of intrasphincteric injection of Clostridium botulinum toxin. Methods Retrospective review of the medical records of 20 patients (8 male, mean 5.8 ± 4.2 years) with severe chronic constipation and IAS achalasia. Each patient received four-quadrant, intrasphincteric injections of botulinum toxin at a dose of 15–25U per quadrant. Patients were reassessed 4 weeks-18 months after injection. We compared the clinical characteristics of these patients to 20 consecutive children (14 male, mean age 8.1 + 4.6 y) with functional constipation (control group). Results The children with IAS achalasia had earlier onset of symptoms, less fecal soiling, and less withholding behavior than the control children. Response to botulinum injection was rated excellent by the parents in 60% and by the physician in 35% of children. There was wide individual variability in the frequency of defecation after therapy. Duration of response ranged from 1 week to 18 months. Conclusions Children with IAS achalasia have clinical characteristics differentiating them from children with functional constipation. Intra-anal injection of botulinum toxin is a safe and effective short-term treatment for these children.

Coordinated interdisciplinary management of pediatric intestinal failure: A 2-year review

BACKGROUND/PURPOSE Intestinal failure is a complex metabolic process that results from malabsorption and malnutrition and provides challenges for a variety of pediatric subspecialists. The purpose of this study was to evaluate the effect of coordinated interdisciplinary team management of children with intestinal failure on nutritional outcome measures. METHODS The Intestinal Care Center (ICC) is staffed with an interdisciplinary team of pediatric specialists including a gastroenterologist, pediatric surgeon, transplant surgeon, clinical dietitians, and a nutrition support nurse. Using an established registry, the authors conducted a comprehensive evaluation of patient data including anthropometric measures, organ system function, and mode of nutrition support. Disease-associated complications including micronutrient deficiencies, growth delay, and death also were monitored. Nutritional outcome was assessed by transition from enteral to oral feeding, cessation of total parenteral nutrition (TPN), and maintenance of linear growth. RESULTS Since the inception of the ICC in 1996, 103 patients (69 boys, 34 girls) with intestinal failure have been evaluated with a median age of 2.6 years (range, 0.2 to 21.3 years). Mode of nutritional therapy on initial consultation included TPN (n = 76, 74%), enteral feedings (n = 6, 6%) and oral intake (n = 21, 20%). After intensive management of the 76 patients who were TPN dependent, 22 (29%) subsequently have been weaned from TPN (duration, 0.2 to 17.5 years) to oral (n = 14), oral-enteral (n = 4) or enteral feedings (n = 4). Of the 6 patients who were receiving enteral feedings, 4 (67%) were transitioned to oral feedings. Sixty-eight patients (66%) had evidence of hepatic disease. Of these, 10 underwent transplant, and 23 died (2 posttransplant). Linear growth velocity of neither pre- nor postpubescent patients significantly improved during the 2-year study period. CONCLUSION Data registry establishment and concurrent interdisciplinary team management of children with intestinal failure provides for innovative treatment approaches and a foundation for retrospective or prospective assessment of children with disease.

The Influence of Down's Syndrome on the Management and Outcome of Children With Hirschsprung's Disease

BACKGROUND Children with Downs syndrome (DS) have a reportedly poorer outcome after treatment of Hirschsprungs disease (HD) compared with control children. Because of overall improvements in their management, the authors hypothesized that the diagnosis of DS would not influence outcome after the management of HD. METHODS Consecutive children with HD (1995 through 2002) were collected prospectively then divided retrospectively into those with DS and controls (C). Patients who underwent surgery at another institution and those with total colonic aganglionosis were excluded. RESULTS Of 66 patients, 9 had DS. Mean age at diagnosis, gender, racial distribution, gestational age, and proximity to our center were similar between groups. Presenting symptoms, location of the transition zone, and type of initial operation were similar. Patients with DS had significantly more comorbidities than controls, which generated significantly greater treatment costs and a higher mortality rate. However, with an average of 22 months of follow-up, the overall outcome including postoperative complications, enterocolitis, and constipation was similar. CONCLUSIONS These data suggest that in contrast to earlier reports, DS has minimal influence on surgical outcome of patients with HD. Although the overall cost of treating patients with DS is greater, this mainly reflects the impact of managing comorbidities.

Insulinlike growth factor 1 and insulinlike growth factor 3: Indices of intestinal failure in children

BACKGROUND/PURPOSE A number of pediatric patients with short bowel syndrome (SBS) manifest growth failure despite aggressive nutritional support. Exogenous growth hormone (GH) therapy in children with SBS has proved disappointing. The purpose of this study was to determine if there were characteristic patterns of GH, IGF-1, or IGFBP-3 levels in pediatric SBS patients with profound growth failure in an effort to elucidate an early strategic approach to management of SBS in the subpopulation. METHODS Forty patients (29 boys, 11 girls; mean age, 5.3 years; range, 0.5 to 18.6 years) with SBS (<30% total bowel length) who received intensive nutrition support and follow-up underwent serological tests for GH, IGF-1, IGFBP-3, and thyroid function. Height (HT), weight (WT), and bone age were assessed relative to age-appropriate percentiles. Growth failure was defined as a HT and WT at less than the fifth percentile and bone age > or = 2 standard deviations below actual age. Residual small bowel length was determined by review of pathological and operative reports. Comparisons between the growth factors, bowel length, and anthropometric data were analyzed by chi2. RESULTS Two distinct subgroups of patients emerged from our study. Thirty-eight percent of patients (n = 11) had growth failure by anthropometry that was associated significantly with low IGF-1 independently and with both IGF-1 and IGFBP-3 levels (P< 0.05). There were no significant associations with GH level, thyroid function, small bowel length, or the amount of parenteral versus enteral intake in either subgroup of these patients. Low IGF-1 and IGFBP-3 but not GH levels may be indices of intestinal failure in pediatric SBS. Growth in this subpopulation is refractory to aggressive standard approaches to nutritional support and may require early interventions. CONCLUSION Exogenous IGF-1 and IGFBP-3, not GH, may be beneficial to treat this subpopulation.

First reported experience with intramuscular diaphragm pacing in replacing positive pressure mechanical ventilators in children

PURPOSE Diaphragm pacing (DP) has been shown to successfully replace mechanical ventilators for adult tetraplegic patients with chronic respiratory insufficiency. This is the first report of DP in ventilator-dependent children. METHODS This was a prospective interventional experience under institutional review board approval. Diaphragm pacing involves outpatient laparoscopic diaphragm motor point mapping to identify the site where stimulation causes maximum diaphragm contraction with implantation of 4 percutaneous intramuscular electrodes. Diaphragm conditioning ensues to wean the child from the ventilator. RESULTS Six children were successfully implanted ranging from 5 to 17 years old with the smallest 15 kg in weight. Length of time on mechanical ventilation ranged from 11 days to 7.6 years with an average of 3.2 years. In all patients, DP provided tidal volumes above basal needs. Five of the patients underwent a home-based weaning program, whereas one patient who was implanted only 11 days post spinal cord injury never returned to the ventilator with DP use. Another patient was weaned from the ventilator full time but died of complications of his underlying brain stem tumor. The remaining patients weaned from the ventilator for over 14 hours a day and/or are actively conditioning their diaphragms. CONCLUSION Diaphragm pacing successfully replaced mechanical ventilators, which improves quality of life.

Colon Cleansing With Oral Sodium Phosphate in Adolescents: Dose, Efficacy, Acceptability, and Safety

BACKGROUND AND AIMS:Standardized bowel preparation in children and adolescents has not been established. Our aim was to compare two bowel preparation regimens and determine which was more effective, acceptable, and safer for children undergoing colonoscopy.METHODS:We compared the efficacy and acceptability of a 1-day regimen with oral sodium phosphate solution (NaP solution) (1 mL/kg/day, maximum 90 mL in two divided doses; regimen A) to our standard 3-day regimen magnesium citrate (4 mL/kg/day × 3 days, maximum 237 mL, followed by an enema the morning of colonoscopy; regimen B). After informed consent was obtained, 48 children were randomized (N = 25, 23, respectively). Weight, electrolytes, calcium, phosphorus, and magnesium were measured at screening and the day of the colonoscopy. Questionnaires were given to assess acceptability and adverse events. Endoscopists rated the quality of bowel preparation on a 4-level scale from excellent to poor.RESULTS:Median age and weight at screening were 14 yr, 53 kg, and 15 yr, 51 kg in regimen A and B, respectively. No statistical significance was observed in electrolytes, phosphorus, or adverse events apart from higher nausea intensity in regimen A (P= 0.012). Bowel cleansing was similar between groups (71% excellent or good). Subjects were more willing to repeat regimen A than B (77% vs 32%, respectively, P < 0.006). All 10 subjects who received regimen A and had prior colonoscopies using regimen B, preferred regimen A.CONCLUSIONS:In a selected group of otherwise healthy children and adolescents over 10.5 yr and above 34 kg, 1-day oral NaP solution was more acceptable than 3-day magnesium citrate with an enema, and both regimens were found to be safe and efficacious.

Serum growth factors and growth indices pre- and post-pediatric intestinal transplantation

BACKGROUND/PURPOSE Although intestinal transplantation (ITx) has succeeded in liberating children with intestinal failure from total parenteral nutrition (TPN), positive growth has yet to be achieved in the majority of patients. This investigation aims to evaluate levels of serum growth factors as they relate to growth parameters and nutritional outcomes. METHODS Serum measures of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) that had been obtained before and after transplantation were reviewed (with Institutional Review Board approval) in a subset of pediatric ITx recipients. Z-scores for weight and height were calculated at transplant and biannually thereafter for 2 years. RESULTS Five children received a small bowel/liver transplant between August 1996 and March 2000 (median age, 1.3 years). Before transplantation, levels of IGF-1 and IGFBP-3 were low in 60% and 67% of patients, respectively. Posttransplant levels of these growth factors were within normal limits or elevated in all but 2 patients (IGFBP-3 only). A positive trend in z-scores was observed in just one of 5 patients for weight and in 2 of 5 for height/length during the follow-up period. Of the 3 patients who experienced negative linear growth velocity over time, 2 had low pretransplant levels of both IGF-1 and IGFBP-3. All patients were weaned from TPN within 3 months after transplant. CONCLUSIONS Pretransplant levels of growth mediators may be predictive factors in children who will require an intensive regimen of nutritional rehabilitation posttransplant to promote the growth process. Absorption studies may aid in determining the appropriate nutrient substrates for the post-ITx population.

Advanced neuroblastoma impairs dendritic cell function in adoptive immunotherapy.

BACKGROUND/PURPOSE The authors previously described the complete regression of established neuroblastoma (NB) by the adoptive transfer of syngeneic interleukin-12 transduced dendritic cells (DC) from naive mice. However, some malignancies, like NB, abrogate DC immunostimulation. The authors hypothesize that IL-12 transduction of DC from NB-bearing mice will have the same antitumor properties. METHODS A/J mice (n = 32) with established NB received peritumoral injection of 1 x 10(6) DC (DC, IL-12 DC, day 7 IL-12 DC or day 14 IL-12 DC) on day 7. Tumor growth, phenotype, and ability to induce NK and T cell activity were measured. RESULTS Vaccination with naive admIL-12 DC resulted in 100% tumor regression and prolonged survival. Transduced DC induced only partial responses in 75% (day 7) and 25% (day 14) of animals. No differences in phenotype or effector cell activation were noted between admIL-12DC in tumor-bearing or naive mice. CONCLUSIONS IL-12 DC from tumor-bearing animals have a decreased ability to induce antitumor activity against established murine NB. This decreased capacity appears to be related to the duration of exposure to tumor because day 14 transduced DC had less of an effect than day 7 DC, despite similar phenotypes and ability to activate immune effector cells.