- Email: [email protected]
Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition
Journal of Pediatric Surgery (2013) 48, 333–338
www.elsevier.com/locate/jpedsurg
Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition Mikko P. Pakarinen a,⁎, Annika Kurvinen a , Antti I. Koivusalo a , Tarja Ruuska b , Heikki Mäkisalo c , Hannu Jalanko d , Risto J. Rintala a a
Section of Pediatric Surgery, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Finland Section of Pediatrics, Tampere University Central Hospital, Tampere, Finland c Department of Surgery, Helsinki University Central Hospital and University of Helsinki, Finland d Section of Pediatrics, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Finland b
Received 5 November 2012; accepted 12 November 2012
Key words: Chronic intestinal pseudo-obstruction; Hirschsprung disease; Intestinal failure; Intestinal failure associated liver disease; Intestinal transplantation
Abstract Aim: The aim of this study was to characterize outcomes of children with severe intestinal motility disorders (IMD) requiring parenteral nutrition (PN). Methods: Twenty consecutive children with primary IMD requiring long-term PN between 1984 and 2010 were included. Median (interquartile range) follow-up was 13.1 (5.2–20.1) years. Treatment, PN dependence, growth, nutritional status, liver function, and survival were assessed. Results: Underlying etiology included chronic intestinal pseudo obstruction (CIPO; n = 8) and Hirschsprung disease with extensive aganglionosis (n = 12). CIPO and aganglionosis patients had 100 (86–100%) and 29 (19–40%) of age-adjusted small bowel length remaining, respectively. In order to facilitate enteral tolerance and avoid PN-associated liver disease, short aganglionic segment (40 cm) was left in situ in four of five cases, with aganglionosis extending to duodenojejunal flexure combined with Ziegler myectomy–myotomy in two. Six of seven children with aganglionosis extending into mid small intestine underwent staged jejunoanal pull-through. Feeding/venting gastrostomies (n = 13) or jejunostomies were commonly employed. Probability of PN dependence owing to IMD was markedly increased in relation to short bowel syndrome (70 versus 19% at 5 years, P b 0.0001). Two (10%) patients developed end-stage liver disease. A total of 11 (55%) patients (5 CIPO and 6 aganglionosis) weaned off PN after 8.2 years (1.8–17 years), including two patients after intestinal transplantation (ITx). Two children died before ITx-era giving overall survival of 90%. Survivors had well-preserved liver function, growth, and nutritional status. Conclusions: Despite high PN dependence, long-term survival is achievable in the majority of children with IMD requiring PN. A wide repertory of surgical options including ITx is required for optimal outcomes. © 2013 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Children's Hospital, Section of Pediatric Surgery, Helsinki University Central Hospital, University of Helsinki, Box 281, FIN00029 HUS, Finland. Tel.: +358 50 427 2981; fax: + 358 9 471 76717. E-mail address: [email protected] (M.P. Pakarinen). 0022-3468/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpedsurg.2012.11.010
334 Intestinal failure refers to any intestinal disease requiring parenteral nutrition (PN) for maintenance of adequate nutrition, growth and survival [1]. In addition to short bowel syndrome (SBS), severe intestinal motility disorders, including chronic intestinal pseudo-obstruction (CIPO) and extensive intestinal aganglionosis owing to Hirschsprung disease (HD) are among the most important underlying diseases [1]. These are characterized by permanent or recurrent chronic functional obstruction in the absence of mechanical occlusion owing to impaired intestinal motor and propulsive activity leading to inadequate oral intake and necessitating PN [1–3]. Malabsorption is further aggravated by small bowel bacterial overgrowth and increased intestinal losses [2,3]. CIPO is a very heterogeneous group of neuropathic and myopathic forms [2–7], while extensive aganglionosis represents a rare form of total colonic HD with extended jejunoileal involvement [8–10]. In these patient groups long-term PN-dependence is 60–80% and mortality from 20 to 30% up to 66% is reported before adulthood, being markedly higher than in SBS [4–6,8–10]. The main management goals include improvement of intestinal passage and propulsive function, while maintaining adequate nutrition (2,11,). The effectiveness of prokinetic drugs is inconsistent [2,11,12] and the mainstay of treatment is therefore nutritional support. Every effort should be made to avoid life-threatening complications of long-term PN, such as intestinal failure associated liver disease (IFALD), septicemia, and loss of venous access sites when intestinal transplantation (ITx) serves as a salvage therapy [13–15]. Non-transplant surgery can relieve intestinal obstruction, facilitate enteral tolerance and provide prerequisite for weaning off PN with preserved mouth-to-anus intestinal continuity. We aimed to analyze our experience of surgical treatment and outcomes of children with severe intestinal motility disorders who required long-term PN.
1. Patients and methods The medical records of children with severe intestinal motility disorders treated and followed-up by our center between 1984 and 2011 were reviewed. Inclusion criteria were a diagnosis of CIPO or extensive intestinal aganglionosis and PN requirement for longer than 3 months. CIPO was defined as recurrent or chronic intestinal obstructive symptoms with radiological findings suggestive of obstruction without occluding lesions after endoscopic, surgical or radiological examination [11]. Extensive aganglionosis was defined as the absence of ganglion cells extending to or above the mid region of the small bowel. Exclusion criteria were CIPO without PN requirement (n = 1) and total colonic aganglionosis extending to the distal ileum (n = 10). In total, 20 consecutive children were enrolled. Data records included gestational age, birth weight, onset of symptoms, familial history of the disease, results of
M.P. Pakarinen et al. diagnostic investigations, surgical procedures, length of the remaining small intestine and colon, type of intestinal circuit, nutritional history, dependence of PN, listing for transplantation and survival. Percentage of age-adjusted small intestinal length was assessed according to Struijs et al. [16]. The proportion of the remaining colon was defined as previously described [16,17]. Growth and serum concentrations of cholesterol, albumin, vitamins A and E, bilirubin and alanine aminotransferase (ALT) were measured at last follow-up. Height and weight were expressed as z-scores in relation to growth standards of the age- and gender matched Finnish population.
1.1. Nutritional and medical management Cyclic nocturnal PN infusions were delivered at home whenever possible and were adjusted according to individual needs as described previously [18,19]. Excessive PN fat was avoided (b 1 g/kg/d) and fat infusions were limited to every other day or less frequently and recently fish oil-based emulsions were used if biochemical signs of impeding IFALD were observed [18,19]. Unrestricted oral intake with low residue, low fiber diet was preferred. Enteral nutrition was actively endorsed by providing bolus or continuous formula feeding via gastrostomy or jejunostomy as tolerated. Symptomatic bacterial overgrowth was empirically treated with rotating enteral antimicrobial therapy [20]. Among CIPO patients and in patients with retained aganglionic small bowel prokinetic medication, mainly cisapride and erythromycin were administered in an attempt to improve intestinal propulsive activity and enteral tolerance.
1.2. Principles of surgical management Among CIPO patients, any unnecessary laparotomies and especially small intestinal resections were avoided. Neonates, whose aganglionosis extended to or above the duodenojejunal flexure, were managed by retaining the proximal part of aganglionic jejunum [21,22]. After histological confirmation of the transitional zone, the entire aganglionic bowel was resected excluding about 40 cm of the proximal jejunum, which was brought out as a jejunostomy. If no sufficient intestinal passage was observed in few weeks, antimesenteric myectomy–myotomy of the aganglionic segment was performed as described by Ziegler [22]. Jejunoanal endorectal pull-through was performed whenever possible after stabilization of the intestinal and liver function and confirmation of adequate nutrition and progressive weight gain.
1.3. Intestinal transplantation Allografts were recruited from size-matched cadaveric donors and included the small intestine and the right colon as the patients lacked native colon. Grafts were revascularized
Severe pediatric intestinal motility disorders requiring PN by the superior mesenteric artery and venous outflow was reconstructed through the portal vein or the infrarenal vena cava. Ischemia times were 4.0 and 4.7 hours. A covering loop-ileostomy was taken down about 1 year following transplantation allowing feasibly frequent endoscopic graft monitoring during the first postoperative year [13]. After induction with anti-interleukin 2-receptor monoclonal antibody (basiliximab), tacrolimuse-based triple therapy including methyl prednisolone and azathioprine was used for maintenance immunosuppression. Antimicrobial bowel decontamination was administered for 1 month and anticytomegalovirus prophylaxis was continued for 6 months. The first ITx was performed in 2009 within our nation-wide ITx program.
1.4. Short bowel syndrome controls A group of 40 SBS children with remaining small bowel length b 123 cm and treated at our center during the same study period was included in order to compare with children with severe intestinal motility disorders [21,23]. Twenty SBS control children and six dysmotility patients have been included in our previous reports [21,23]. The ethical committee of the hospital approved the study protocol.
1.5. Statistical analysis Unless otherwise stated the data are given as the median and interquartile range (IQR). Frequencies were compared with the Fisher exact test. The Mann–Whitney test was used to compare continuous variables between the groups. The Kaplan–Meier method with a Mantel–Cox log rank test was used to evaluate cumulative risks of remaining on PN and survival. The duration of PN was calculated from the date of PN start to end of follow-up, cessation of PN, ITx or death. Survival time extended from birth to the end of follow-up or death. A P value b 0.05 was considered statistically significant.
335 Table 1
Patient characteristics.
Variable
CIPO
Aganglionosis
Number (males) Symptoms from birth PN dependence from birth Familial disease Birth weight (g) Gestational age (weeks) Follow-up (years)
8 (6) 8/8 6/8
12 (6) 12/12 12/12
1/8 3394 (3220–3580) 39 (39–40) 19.0 (5.9–22.2)
1/12 3337 (3028–3596) 39 (39–40) 10.2 (3.5–15.8)
Data are frequencies or medians (IQR); PN, parenteral nutrition; CIPO, chronic intestinal pseudo-obstruction. There were no significant differences between the groups.
2.1. Operative approach and anatomy of the remaining bowel 2.1.1. CIPO Overall, CIPO patients had 100% (86–100%) of small bowel remaining and six had most of the colon preserved. Six of the eight CIPO patients had an endoscopically placed gastrostomy, which was combined with a jejunostomy in one case. Permanent end-ostomy was performed in four after prolonged intolerance of enteral feedings despite optimized medical therapy (Table 2). Two patients on the ITx waiting list underwent colectomy in hope to prevent recurrent sepsis episodes presumed to be caused by bacterial translocation of enteric pathogens without clear-cut response. 2.1.2. Extensive aganglionosis Aganglionosis extended to the region of the duodenojejunal flexure in five (panintestinal aganglionosis) and to the mid small intestine in seven cases. Extensive aganglionosis necessitated significant small intestinal resections in addition to colectomy: the median absolute and age-adjusted length of the remaining small bowel was 85 cm and 29%, respectively
Table 2 Intestinal anatomy among patients with chronic intestinal pseudo-obstruction (CIPO) and extensive aganglionosis.
2. Results
Variable
In total, 20 patients at median age of 13.1 (5.2–20.1) years were enrolled (Table 1). Half had associated disorders, which included megacystis (n = 2), gastric volvulus and splenic torsion (n = 1), malrotation volvulus (n = 1) and esophageal atresia among CIPO patients and hair-cartilage hypoplasia (n = 2), Shah–Waardenburg syndrome (n = 1), central hypoventilation syndrome and thoracic neuroblastoma (n = 1) and vesicoureteral reflux (n = 1) among HD patients. Three of the CIPO patients were classified as neuropathic form, one had mixed neuromyopathic form, no distinctive histological features were found in two, and two had no full thickness bowel biopsy available.
Remaining small bowel Absolute (cm) Age-adjusted (%) Ileocecal valve preserved Remaining colon (%) Intestinal circuit Intestinoanal continuity Jejunostomy Ileostomy Sigmoidostomy
CIPO (n = 8)
Aganglionosis (n = 12)
239 (213–410) 100 (86–100) 6/8 80 (0–100)
85 (55–150) ⁎ 29 (19–40) ⁎ 0/12 ⁎ 0⁎
4/8 0/8 3/8 1/8
6/12 6/12 0/12 0/12
Data are frequencies and medians (IQR). ⁎ P b 0.05 between CIPO and aganglionosis groups.
336 (Table 2). The exact location of the transition zone in the five patients with panintestinal aganglionosis was duodenum (n = 2), duodenojejunal flexure (n = 2), and 30 cm distal to the duodenojejunal flexure (n = 1). In order to facilitate enteral tolerance and avoid PN-associated liver disease, a short aganglionic segment (about 40 cm) was left in situ in four of five cases combined with Ziegler myectomy–myotomy in two. Six of seven patients with aganglionosis extending to the mid small intestine underwent staged jejunoanal pullthrough with covering ostomy at median age of 13.3 (10.5– 17.6) months. Pull-through operations included five endorectal procedures and one Lester–Martin–Duhamel procedure. Three of the endorectal pull-through procedures were straight and two with J-pouch. Covering ostomy was closed 2.3 (1.5–26.4) months after the primary procedure. Altogether, intestinoanal continuity was restored in half of the patients with extensive ganglionosis and seven of them (70%) had feeding/venting gastrostomy (n = 6) or jejunostomy (n = 1) (Table 2). Two Hirschsprung patients underwent tapering enteroplasty of a dilated aganglionic and ganglionic small intestinal segment at age of 5 and 22 years owing to symptomatic bacterial overgrowth followed by functional improvement in both allowing significant reduction or avoidance of PN, respectively.
2.2. Medical treatment All CIPO patients and those with retained aganglionic small bowel had received prokinetic medication, mainly cisapride during and/or between pseudo-obstruction exacerbations with inconsistent response. Rotating enteral antimicrobial therapy for bacterial overgrowth, including different combinations of metronidazole, ciprofloxacin, amoxicillin and fluconazol had been administered to all patients at some time point [6,11,20]. Two CIPO patients on the ITx waiting list received cycled bowel decontamination with tobramycin, colistin and amphotericin for recurrent sepsis episodes [24]. Ten (63%) received proton-pump inhibitors, and two HD patients used loperamide in order to slow down rapid intestinal transit following resection of the aganglionic segment extending to the mid small bowel.
M.P. Pakarinen et al. Table 3 Parenteral nutrition dependence and survival among patients with chronic intestinal pseudo-obstruction (CIPO) and extensive aganglionosis. Variable
CIPO (n = 8)
Aganglionosis All (n = 20) (n = 12)
Weaned off PN After ITx Duration of PN (years) All patients Before weaning off PN Survival
5/8 1/8
6/12 1/12
11/20 2/20
3.8 (0.8–16.8) 4.8 (2.0–11.1) 4.8 (1.8–14.8) 15.8 (0.2–18.0) 6.6 (2.1–15.6) 8.2 (1.7–17.4) 8/8
10/12
18/20
Data are frequencies and medians (IQR); PN, parenteral nutrition; ITx, intestinal transplantation. There were no significant differences between the groups.
adjusted length of the remaining small bowel was significantly (P b 0.05) greater among HD patients who weaned off PN [150 (104–170) cm and 35% (35–54%), respectively] compared to those who remained PN dependent [60 (43–68) cm and 21% (15–25%), respectively].
2.4. Intestinal transplantation and survival Overall, two patients with HD died of end-stage liver failure (n = 1) and sepsis (n = 1) before the ITx-era giving an overall survival of 90% (Fig. 2). One patient with panintestinal aganglionosis and one with CIPO received intestinal allograft at the age of 15 and 17 years after lifelong PN owing to progressive cholestasis and recurrent sepsis episodes associated with loss of venous access sites, respectively. At the time of study both transplanted patients were alive on full enteral feeds without any parenteral support 25 and 15 months after ITx. In addition, one CIPO patient and one with panintestinal aganglionosis were listed
2.3. Parenteral nutrition-dependence The overall duration of PN was 4.8 (1.8–15) years without a significant difference between the two groups (Table 3). Actuarial PN dependence probability was 90, 70 and 60% at 1, 5 and 10 years, respectively (Fig. 1). Probability of PD dependence owing to intestinal motility disorders was markedly increased in relation to SBS (70 versus % at 5 years, P b 0.0001). In total, 11 (55%) patients (5 CIPO and 6 aganglionosis) weaned off PN after median of 8.2 years on PN including 2 patients (1 CIPO and 1 aganglionosis) after ITx (Table 3). Of note, none of the patients with panintestinal aganglionosis weaned off PN without ITx. Absolute and age-
Fig. 1 Probability of remaining on parenteral nutrition (PN) in patients with intestinal motility disorder (black cross) and short bowel syndrome (open circle).
Severe pediatric intestinal motility disorders requiring PN
Fig. 2 Probability of survival in patients with intestinal motility disorder (black cross) and short bowel syndrome (open circle).
for ITx owing to recurrent episodes of sepsis, dehydration and electrolyte imbalance.
2.5. Growth, nutrition and liver function Growth, nutritional status and liver function are shown in Table 4. Weight gain was well preserved while axial growth was retarded, especially after weaning off PN. Serum levels of fat-soluble vitamins, bilirubin and ALT were within the normal range. None of the surviving patients had serum bilirubin over 21 μmol/l, while six patients, two on PN and four after weaning off PN, had mildly increased serum ALT concentration between 45–88 U/l.
3. Discussion In line with previous reports on pediatric CIPO [4–7], non-transplant surgery in the present series included palliative procedures such as feeding/venting gastro- and jejunostomies and decompressive intestinal ostomies providing relief of obstructive symptoms in approximately half
Table 4
337 of the patients. These operations were undertaken only after prolonged intolerance of enteral feedings despite optimized medical therapy although prokinetics have a limited value in treatment of these patients [2,6,11]. Small intestinal resections were rigorously avoided in order to prevent development of IFALD and to maintain abdominal domain should ITx become necessary [21]. From this evaluation we specifically excluded the HD patients with total colonic aganglionosis extending to the distal ileum, since management of these patients is relatively straightforward without significant risk of long-term PNdependence or excess mortality [25–27]. Only the patients with extensive aganglionosis extending to or above mid small intestine were included as reflected by the short median length of the remaining small bowel (Table 2). As in CIPO, percutaneous gastrostomies were liberally used mainly to enhance enteral nutrition and widespread small intestinal resections were actively avoided even by leaving aganglionic small bowel segment in situ in the most extensive cases for protection of the liver from development of IFALD and maintenance of abdominal domain [21]. This policy of liver protection combined with limited parenteral fat and active endorsement of enteral nutrition appeared efficient as only two patients (10%) in the entire series developed cholestasis/ IFALD. Cholestasis resolved after successful ITx in the other and the other, who developed end stage liver failure, was referred to us after having undergone resection of the entire aganglionic bowel leaving only 30 cm of proximal small intestine ending as jejunostomy. Moreover, all 18 (90%) survivors had normal serum bilirubin without signs of IFALD at median age of 14 years (Table 4). All survivors received cycled enteral antibiotics prior to ITx in order to treat symptoms of bacterial overgrowth such as abdominal bloating, diarrhea associated with worsening intolerance of enteral feeding or to prevent recurrent sepsis episodes [2,6,11,20,24]. Dilated small intestinal segment proved to be a source of bacterial overgrowth in two patients with extensive aganglionosis. Dilated segments were successfully treated by simple tapering, instead of serial transverse enteroplasty routinely used in SBS [21], to avoid
Growth, nutrition and liver function variables during and after weaning off PN at last follow-up (median age 13.9 years).
Variable
On PN (n = 7)
Weaned off PN (n = 10)
Reference
Height z score Weight z score Serum cholesterol, mmol/l Serum albumin, g/l Serum vitamin A, μmol/l Serum vitamin E, μmol/l Serum bilirubin, μmol/l Serum ALT, U/l
− 0.3 (− 0.5 to 0.1) 0 (− 0.5 to 1.0) 2.4 (2.0 to 3.0) 33 (32 to 35) 1.2 (0.7 to 1.3) 19 (17 to 26) 3 (2 to 4) 37 (17 to 64)
− 2.0 (− 2.0 to 0.9) ⁎ − 0.8 (− 1.0 to 0.0) 2.6 (2.2 to 2.8) 38 (30 to 40) 1.8 (1.4 to 2.0) ⁎ 24 (12 to 28) 6 (5 to 9) ⁎ 35 (31 to 46)
0 0 2.5–5.0 37–51 1–3 12–40 b 20 b 40
Data are median (IQR); ALT, alanine aminotransferase; PN, parenteral nutrition. ⁎ P b 0.05 between during and after weaning off PN.
338 postoperative functional obstruction of the dysmotile bowel. Antimicrobial treatment of bacterial overgrowth should be carefully pondered because of risk of multiresistant bacterial strains. Unfortunately, it is often required because of frequent episodes of bacterial overgrowth in CIPO and associated enterocolitis in patients with HD. Probability of remaining on PN at 5 years was 70% without differences between patients with CIPO or extensive aganglionosis (Fig. 1 and Table 3). This is strikingly higher than the respective figure of 19% in SBS patients treated at the same time period, confirming that children with motility disorders are less likely to wean off PN than those with SBS [21]. Comparable findings have been reported for adult CIPO patients [11]. Not surprisingly, in patients with extensive aganglionosis length of the remaining small intestine was a significant determinant of PN duration. According to previous reports none of the patients with panintestinal aganglionosis weaned off PN without ITx [13]. Overall survival was 90%, 8 of 8 in CIPO and 10 of 12 among patients with extended aganglionosis comparing well with previous reports. In CIPO, mortality rates of 10–32% before reaching adulthood have been reported with overall PN-dependency of 62–74% [4–6]. Extension of aganglionosis strongly modifies mortality in HD being up to 66% in patients with total intestinal aganglionosis [8–10]. In our material, ITx granted extended survival with benefit of cessation of PN for two patients, and after completion of this study one additional CIPO patient has been successfully transplanted. In conclusion, in our experience most of the children with severe intestinal motility disorders remain PN-dependent, while a proportion of them develop PN failure necessitating ITx. Surgical care of these patients entails a critical approach with careful planning of each procedure while strictly avoiding unnecessary ones. Long-term survival, a low incidence of IFALD and acceptable growth and nutrition are achievable with modern medical and surgical care including ITx in this group of children.
References [1] Goulet O, Ruemmele F. Causes and management of intestinal failure. Gastroenterology 2006;130:S16-28. [2] Di Lorenzo C, Youssef NN. Diagnosis and management of intestinal motility disorders. Semin Pediatr Surg 2010;19:50-8. [3] Antonucci A, Fronzoni L, Cogliandro L, et al. Chronic intestinal pseudo-obstruction. World J Gastroenterol 2008;21:2953-61. [4] Mousa H, Hyman PE, Cocjin J, et al. Long-term outcome of congenital intestinal pseudoobstruction. Dig Dis Sci 2002;47:2298-305. [5] Heneyke S, Smith VV, Spitz L, et al. Chronic intestinal pseudoobstruction: treatment and long-term follow up of 44 patients. Arch Dis Child 1999;81:21-7.
M.P. Pakarinen et al. [6] Faure C, Goulet O, Ategbo S, et al. Chronic intestinal pseudoobstruction syndrome. Clinical analysis, outcome, and prognosis in 105 children. Dig Dis Sci 1999;44:953-9. [7] Vargas JH, Sachs P, Ament ME. Chronic intestinal pseudo-obstruction syndrome in pediatrics. Results of a national survey by members of the North American Society of Pediatric gastroenterology and Nutrition. Journal Pediatr Gastroenterol Nutr 1988;7:323-32. [8] Ruttenstock E, Puri P. A meta-analysis of clinical outcome in patients with total intestinal aganglionosis. Pediatr Surg Int 2009;25:833-9. [9] Kimura O, Ono S, Furukawa T, et al. Management strategies for infants with total intestinal aganglionosis. J Pediatr Surg 2009;44:1564-7. [10] Saxton ML, Ein SH, Hoehner J, et al. Near-total intestinal aganglionosis: long-term follow-up of a morbid condition. J Pediatr Surg 2000;35:669-72. [11] Amiot A, Joly F, Alves A, et al. Long-term outcome of chronic intestinal pseudo-obstruction adult patients requiring home parenteral nutrition. Am J Gastroenterol 2009;104:1262-70. [12] Panganamamula KV, Parkman HP. Chronic intestinal pseudoobstruction. Curr Treat Options Gastroenterol 2005;8:3-11. [13] Sauvat F, Grimaldi C, Lacaille F, et al. Intestinal transplantation for total intestinal aganglionosis: a series of 12 consecutive children. J Pediatr Surg 2008;43:1833-8. [14] Loinaz C, Rodriquez MM, Kato T, et al. Intestinal and multivisceral transplantation in children with severe gastrointestinal dysmotility. J Pediatr Surg 2005;40:1598-604. [15] Bond GJ, Reyes JD. Intestinal transplantation for total/near-total aganglionosis and intestinal pseudo-obstruction. Semin Pediatr Surg 2004;13:286-92. [16] Struijs M-C, Diamond IR, de Silva N, et al. Establishing norms for intestinal length in children. J Pediatr Surg 2009:933-8. [17] Mitchell JE, Breuer RI, Zuckerman L, et al. The colon influences ileal resection diarrhea. Dig Dis Sci 1980;25:33-41. [18] Kurvinen A, Nissinen MJ, Andersson S, et al. Parenteral plant sterols and intestinal failure-associated liver disease in neonates: a prospective nationwide study. J Pediatr Gastroenterol Nutr 2012;54:803-11. [19] Kurvinen A, Nissinen MJ, Gylling H, et al. Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. J Pediatr Gastroenterol Nutr 2011;53:440-6. [20] Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology 2006;130: S78-90. [21] Pakarinen MP, Koivusalo AI, Rintala RJ. Outcomes of intestinal failure—a comparison between children with short bowel and dysmotile intestine. J Pediatr Surg 2009;44:2139-44. [22] Ziegler MM, Royal RE, Brandt J, et al. Extended myectomymyotomy. A therapeutic alternative for total intestinal aganglionosis. Ann Surg 1993;218:504-11. [23] Pakarinen MP, Kurvinen A, Gylling H, et al. Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition. Dig Liver Dis 2010;42:554-9. [24] Dobson R, McGuckin C, Walker G, et al. Cycled enteral antibiotics reduce sepsis rates in pediatric patients on long-term parenteral nutrition for intetinal failure. Aliment Pharmacol Ther 2011;34:1005-11. [25] Escobar MA, Grosfeld JL, West KW, et al. Long-term outcomes in total colonic aganglionosis: a 32-year experience. J Pediatr Surg 2005;40:955-61. [26] Wildhaber BE, Teitelbaum DH, Coran AG. Total colonic Hirschsprung's disease: A 28-year experience. J Pediatr Surg 2005;40:203-7. [27] Menezes M, Pini Prato A, Jasonni V, et al. Long-term clinical outcome in patients with total colonic aganglionosis: a 31-year review. J Pediatr Surg 2008;43:1696-9.
www.elsevier.com/locate/jpedsurg
Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition Mikko P. Pakarinen a,⁎, Annika Kurvinen a , Antti I. Koivusalo a , Tarja Ruuska b , Heikki Mäkisalo c , Hannu Jalanko d , Risto J. Rintala a a
Section of Pediatric Surgery, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Finland Section of Pediatrics, Tampere University Central Hospital, Tampere, Finland c Department of Surgery, Helsinki University Central Hospital and University of Helsinki, Finland d Section of Pediatrics, Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Finland b
Received 5 November 2012; accepted 12 November 2012
Key words: Chronic intestinal pseudo-obstruction; Hirschsprung disease; Intestinal failure; Intestinal failure associated liver disease; Intestinal transplantation
Abstract Aim: The aim of this study was to characterize outcomes of children with severe intestinal motility disorders (IMD) requiring parenteral nutrition (PN). Methods: Twenty consecutive children with primary IMD requiring long-term PN between 1984 and 2010 were included. Median (interquartile range) follow-up was 13.1 (5.2–20.1) years. Treatment, PN dependence, growth, nutritional status, liver function, and survival were assessed. Results: Underlying etiology included chronic intestinal pseudo obstruction (CIPO; n = 8) and Hirschsprung disease with extensive aganglionosis (n = 12). CIPO and aganglionosis patients had 100 (86–100%) and 29 (19–40%) of age-adjusted small bowel length remaining, respectively. In order to facilitate enteral tolerance and avoid PN-associated liver disease, short aganglionic segment (40 cm) was left in situ in four of five cases, with aganglionosis extending to duodenojejunal flexure combined with Ziegler myectomy–myotomy in two. Six of seven children with aganglionosis extending into mid small intestine underwent staged jejunoanal pull-through. Feeding/venting gastrostomies (n = 13) or jejunostomies were commonly employed. Probability of PN dependence owing to IMD was markedly increased in relation to short bowel syndrome (70 versus 19% at 5 years, P b 0.0001). Two (10%) patients developed end-stage liver disease. A total of 11 (55%) patients (5 CIPO and 6 aganglionosis) weaned off PN after 8.2 years (1.8–17 years), including two patients after intestinal transplantation (ITx). Two children died before ITx-era giving overall survival of 90%. Survivors had well-preserved liver function, growth, and nutritional status. Conclusions: Despite high PN dependence, long-term survival is achievable in the majority of children with IMD requiring PN. A wide repertory of surgical options including ITx is required for optimal outcomes. © 2013 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Children's Hospital, Section of Pediatric Surgery, Helsinki University Central Hospital, University of Helsinki, Box 281, FIN00029 HUS, Finland. Tel.: +358 50 427 2981; fax: + 358 9 471 76717. E-mail address: [email protected] (M.P. Pakarinen). 0022-3468/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpedsurg.2012.11.010
334 Intestinal failure refers to any intestinal disease requiring parenteral nutrition (PN) for maintenance of adequate nutrition, growth and survival [1]. In addition to short bowel syndrome (SBS), severe intestinal motility disorders, including chronic intestinal pseudo-obstruction (CIPO) and extensive intestinal aganglionosis owing to Hirschsprung disease (HD) are among the most important underlying diseases [1]. These are characterized by permanent or recurrent chronic functional obstruction in the absence of mechanical occlusion owing to impaired intestinal motor and propulsive activity leading to inadequate oral intake and necessitating PN [1–3]. Malabsorption is further aggravated by small bowel bacterial overgrowth and increased intestinal losses [2,3]. CIPO is a very heterogeneous group of neuropathic and myopathic forms [2–7], while extensive aganglionosis represents a rare form of total colonic HD with extended jejunoileal involvement [8–10]. In these patient groups long-term PN-dependence is 60–80% and mortality from 20 to 30% up to 66% is reported before adulthood, being markedly higher than in SBS [4–6,8–10]. The main management goals include improvement of intestinal passage and propulsive function, while maintaining adequate nutrition (2,11,). The effectiveness of prokinetic drugs is inconsistent [2,11,12] and the mainstay of treatment is therefore nutritional support. Every effort should be made to avoid life-threatening complications of long-term PN, such as intestinal failure associated liver disease (IFALD), septicemia, and loss of venous access sites when intestinal transplantation (ITx) serves as a salvage therapy [13–15]. Non-transplant surgery can relieve intestinal obstruction, facilitate enteral tolerance and provide prerequisite for weaning off PN with preserved mouth-to-anus intestinal continuity. We aimed to analyze our experience of surgical treatment and outcomes of children with severe intestinal motility disorders who required long-term PN.
1. Patients and methods The medical records of children with severe intestinal motility disorders treated and followed-up by our center between 1984 and 2011 were reviewed. Inclusion criteria were a diagnosis of CIPO or extensive intestinal aganglionosis and PN requirement for longer than 3 months. CIPO was defined as recurrent or chronic intestinal obstructive symptoms with radiological findings suggestive of obstruction without occluding lesions after endoscopic, surgical or radiological examination [11]. Extensive aganglionosis was defined as the absence of ganglion cells extending to or above the mid region of the small bowel. Exclusion criteria were CIPO without PN requirement (n = 1) and total colonic aganglionosis extending to the distal ileum (n = 10). In total, 20 consecutive children were enrolled. Data records included gestational age, birth weight, onset of symptoms, familial history of the disease, results of
M.P. Pakarinen et al. diagnostic investigations, surgical procedures, length of the remaining small intestine and colon, type of intestinal circuit, nutritional history, dependence of PN, listing for transplantation and survival. Percentage of age-adjusted small intestinal length was assessed according to Struijs et al. [16]. The proportion of the remaining colon was defined as previously described [16,17]. Growth and serum concentrations of cholesterol, albumin, vitamins A and E, bilirubin and alanine aminotransferase (ALT) were measured at last follow-up. Height and weight were expressed as z-scores in relation to growth standards of the age- and gender matched Finnish population.
1.1. Nutritional and medical management Cyclic nocturnal PN infusions were delivered at home whenever possible and were adjusted according to individual needs as described previously [18,19]. Excessive PN fat was avoided (b 1 g/kg/d) and fat infusions were limited to every other day or less frequently and recently fish oil-based emulsions were used if biochemical signs of impeding IFALD were observed [18,19]. Unrestricted oral intake with low residue, low fiber diet was preferred. Enteral nutrition was actively endorsed by providing bolus or continuous formula feeding via gastrostomy or jejunostomy as tolerated. Symptomatic bacterial overgrowth was empirically treated with rotating enteral antimicrobial therapy [20]. Among CIPO patients and in patients with retained aganglionic small bowel prokinetic medication, mainly cisapride and erythromycin were administered in an attempt to improve intestinal propulsive activity and enteral tolerance.
1.2. Principles of surgical management Among CIPO patients, any unnecessary laparotomies and especially small intestinal resections were avoided. Neonates, whose aganglionosis extended to or above the duodenojejunal flexure, were managed by retaining the proximal part of aganglionic jejunum [21,22]. After histological confirmation of the transitional zone, the entire aganglionic bowel was resected excluding about 40 cm of the proximal jejunum, which was brought out as a jejunostomy. If no sufficient intestinal passage was observed in few weeks, antimesenteric myectomy–myotomy of the aganglionic segment was performed as described by Ziegler [22]. Jejunoanal endorectal pull-through was performed whenever possible after stabilization of the intestinal and liver function and confirmation of adequate nutrition and progressive weight gain.
1.3. Intestinal transplantation Allografts were recruited from size-matched cadaveric donors and included the small intestine and the right colon as the patients lacked native colon. Grafts were revascularized
Severe pediatric intestinal motility disorders requiring PN by the superior mesenteric artery and venous outflow was reconstructed through the portal vein or the infrarenal vena cava. Ischemia times were 4.0 and 4.7 hours. A covering loop-ileostomy was taken down about 1 year following transplantation allowing feasibly frequent endoscopic graft monitoring during the first postoperative year [13]. After induction with anti-interleukin 2-receptor monoclonal antibody (basiliximab), tacrolimuse-based triple therapy including methyl prednisolone and azathioprine was used for maintenance immunosuppression. Antimicrobial bowel decontamination was administered for 1 month and anticytomegalovirus prophylaxis was continued for 6 months. The first ITx was performed in 2009 within our nation-wide ITx program.
1.4. Short bowel syndrome controls A group of 40 SBS children with remaining small bowel length b 123 cm and treated at our center during the same study period was included in order to compare with children with severe intestinal motility disorders [21,23]. Twenty SBS control children and six dysmotility patients have been included in our previous reports [21,23]. The ethical committee of the hospital approved the study protocol.
1.5. Statistical analysis Unless otherwise stated the data are given as the median and interquartile range (IQR). Frequencies were compared with the Fisher exact test. The Mann–Whitney test was used to compare continuous variables between the groups. The Kaplan–Meier method with a Mantel–Cox log rank test was used to evaluate cumulative risks of remaining on PN and survival. The duration of PN was calculated from the date of PN start to end of follow-up, cessation of PN, ITx or death. Survival time extended from birth to the end of follow-up or death. A P value b 0.05 was considered statistically significant.
335 Table 1
Patient characteristics.
Variable
CIPO
Aganglionosis
Number (males) Symptoms from birth PN dependence from birth Familial disease Birth weight (g) Gestational age (weeks) Follow-up (years)
8 (6) 8/8 6/8
12 (6) 12/12 12/12
1/8 3394 (3220–3580) 39 (39–40) 19.0 (5.9–22.2)
1/12 3337 (3028–3596) 39 (39–40) 10.2 (3.5–15.8)
Data are frequencies or medians (IQR); PN, parenteral nutrition; CIPO, chronic intestinal pseudo-obstruction. There were no significant differences between the groups.
2.1. Operative approach and anatomy of the remaining bowel 2.1.1. CIPO Overall, CIPO patients had 100% (86–100%) of small bowel remaining and six had most of the colon preserved. Six of the eight CIPO patients had an endoscopically placed gastrostomy, which was combined with a jejunostomy in one case. Permanent end-ostomy was performed in four after prolonged intolerance of enteral feedings despite optimized medical therapy (Table 2). Two patients on the ITx waiting list underwent colectomy in hope to prevent recurrent sepsis episodes presumed to be caused by bacterial translocation of enteric pathogens without clear-cut response. 2.1.2. Extensive aganglionosis Aganglionosis extended to the region of the duodenojejunal flexure in five (panintestinal aganglionosis) and to the mid small intestine in seven cases. Extensive aganglionosis necessitated significant small intestinal resections in addition to colectomy: the median absolute and age-adjusted length of the remaining small bowel was 85 cm and 29%, respectively
Table 2 Intestinal anatomy among patients with chronic intestinal pseudo-obstruction (CIPO) and extensive aganglionosis.
2. Results
Variable
In total, 20 patients at median age of 13.1 (5.2–20.1) years were enrolled (Table 1). Half had associated disorders, which included megacystis (n = 2), gastric volvulus and splenic torsion (n = 1), malrotation volvulus (n = 1) and esophageal atresia among CIPO patients and hair-cartilage hypoplasia (n = 2), Shah–Waardenburg syndrome (n = 1), central hypoventilation syndrome and thoracic neuroblastoma (n = 1) and vesicoureteral reflux (n = 1) among HD patients. Three of the CIPO patients were classified as neuropathic form, one had mixed neuromyopathic form, no distinctive histological features were found in two, and two had no full thickness bowel biopsy available.
Remaining small bowel Absolute (cm) Age-adjusted (%) Ileocecal valve preserved Remaining colon (%) Intestinal circuit Intestinoanal continuity Jejunostomy Ileostomy Sigmoidostomy
CIPO (n = 8)
Aganglionosis (n = 12)
239 (213–410) 100 (86–100) 6/8 80 (0–100)
85 (55–150) ⁎ 29 (19–40) ⁎ 0/12 ⁎ 0⁎
4/8 0/8 3/8 1/8
6/12 6/12 0/12 0/12
Data are frequencies and medians (IQR). ⁎ P b 0.05 between CIPO and aganglionosis groups.
336 (Table 2). The exact location of the transition zone in the five patients with panintestinal aganglionosis was duodenum (n = 2), duodenojejunal flexure (n = 2), and 30 cm distal to the duodenojejunal flexure (n = 1). In order to facilitate enteral tolerance and avoid PN-associated liver disease, a short aganglionic segment (about 40 cm) was left in situ in four of five cases combined with Ziegler myectomy–myotomy in two. Six of seven patients with aganglionosis extending to the mid small intestine underwent staged jejunoanal pullthrough with covering ostomy at median age of 13.3 (10.5– 17.6) months. Pull-through operations included five endorectal procedures and one Lester–Martin–Duhamel procedure. Three of the endorectal pull-through procedures were straight and two with J-pouch. Covering ostomy was closed 2.3 (1.5–26.4) months after the primary procedure. Altogether, intestinoanal continuity was restored in half of the patients with extensive ganglionosis and seven of them (70%) had feeding/venting gastrostomy (n = 6) or jejunostomy (n = 1) (Table 2). Two Hirschsprung patients underwent tapering enteroplasty of a dilated aganglionic and ganglionic small intestinal segment at age of 5 and 22 years owing to symptomatic bacterial overgrowth followed by functional improvement in both allowing significant reduction or avoidance of PN, respectively.
2.2. Medical treatment All CIPO patients and those with retained aganglionic small bowel had received prokinetic medication, mainly cisapride during and/or between pseudo-obstruction exacerbations with inconsistent response. Rotating enteral antimicrobial therapy for bacterial overgrowth, including different combinations of metronidazole, ciprofloxacin, amoxicillin and fluconazol had been administered to all patients at some time point [6,11,20]. Two CIPO patients on the ITx waiting list received cycled bowel decontamination with tobramycin, colistin and amphotericin for recurrent sepsis episodes [24]. Ten (63%) received proton-pump inhibitors, and two HD patients used loperamide in order to slow down rapid intestinal transit following resection of the aganglionic segment extending to the mid small bowel.
M.P. Pakarinen et al. Table 3 Parenteral nutrition dependence and survival among patients with chronic intestinal pseudo-obstruction (CIPO) and extensive aganglionosis. Variable
CIPO (n = 8)
Aganglionosis All (n = 20) (n = 12)
Weaned off PN After ITx Duration of PN (years) All patients Before weaning off PN Survival
5/8 1/8
6/12 1/12
11/20 2/20
3.8 (0.8–16.8) 4.8 (2.0–11.1) 4.8 (1.8–14.8) 15.8 (0.2–18.0) 6.6 (2.1–15.6) 8.2 (1.7–17.4) 8/8
10/12
18/20
Data are frequencies and medians (IQR); PN, parenteral nutrition; ITx, intestinal transplantation. There were no significant differences between the groups.
adjusted length of the remaining small bowel was significantly (P b 0.05) greater among HD patients who weaned off PN [150 (104–170) cm and 35% (35–54%), respectively] compared to those who remained PN dependent [60 (43–68) cm and 21% (15–25%), respectively].
2.4. Intestinal transplantation and survival Overall, two patients with HD died of end-stage liver failure (n = 1) and sepsis (n = 1) before the ITx-era giving an overall survival of 90% (Fig. 2). One patient with panintestinal aganglionosis and one with CIPO received intestinal allograft at the age of 15 and 17 years after lifelong PN owing to progressive cholestasis and recurrent sepsis episodes associated with loss of venous access sites, respectively. At the time of study both transplanted patients were alive on full enteral feeds without any parenteral support 25 and 15 months after ITx. In addition, one CIPO patient and one with panintestinal aganglionosis were listed
2.3. Parenteral nutrition-dependence The overall duration of PN was 4.8 (1.8–15) years without a significant difference between the two groups (Table 3). Actuarial PN dependence probability was 90, 70 and 60% at 1, 5 and 10 years, respectively (Fig. 1). Probability of PD dependence owing to intestinal motility disorders was markedly increased in relation to SBS (70 versus % at 5 years, P b 0.0001). In total, 11 (55%) patients (5 CIPO and 6 aganglionosis) weaned off PN after median of 8.2 years on PN including 2 patients (1 CIPO and 1 aganglionosis) after ITx (Table 3). Of note, none of the patients with panintestinal aganglionosis weaned off PN without ITx. Absolute and age-
Fig. 1 Probability of remaining on parenteral nutrition (PN) in patients with intestinal motility disorder (black cross) and short bowel syndrome (open circle).
Severe pediatric intestinal motility disorders requiring PN
Fig. 2 Probability of survival in patients with intestinal motility disorder (black cross) and short bowel syndrome (open circle).
for ITx owing to recurrent episodes of sepsis, dehydration and electrolyte imbalance.
2.5. Growth, nutrition and liver function Growth, nutritional status and liver function are shown in Table 4. Weight gain was well preserved while axial growth was retarded, especially after weaning off PN. Serum levels of fat-soluble vitamins, bilirubin and ALT were within the normal range. None of the surviving patients had serum bilirubin over 21 μmol/l, while six patients, two on PN and four after weaning off PN, had mildly increased serum ALT concentration between 45–88 U/l.
3. Discussion In line with previous reports on pediatric CIPO [4–7], non-transplant surgery in the present series included palliative procedures such as feeding/venting gastro- and jejunostomies and decompressive intestinal ostomies providing relief of obstructive symptoms in approximately half
Table 4
337 of the patients. These operations were undertaken only after prolonged intolerance of enteral feedings despite optimized medical therapy although prokinetics have a limited value in treatment of these patients [2,6,11]. Small intestinal resections were rigorously avoided in order to prevent development of IFALD and to maintain abdominal domain should ITx become necessary [21]. From this evaluation we specifically excluded the HD patients with total colonic aganglionosis extending to the distal ileum, since management of these patients is relatively straightforward without significant risk of long-term PNdependence or excess mortality [25–27]. Only the patients with extensive aganglionosis extending to or above mid small intestine were included as reflected by the short median length of the remaining small bowel (Table 2). As in CIPO, percutaneous gastrostomies were liberally used mainly to enhance enteral nutrition and widespread small intestinal resections were actively avoided even by leaving aganglionic small bowel segment in situ in the most extensive cases for protection of the liver from development of IFALD and maintenance of abdominal domain [21]. This policy of liver protection combined with limited parenteral fat and active endorsement of enteral nutrition appeared efficient as only two patients (10%) in the entire series developed cholestasis/ IFALD. Cholestasis resolved after successful ITx in the other and the other, who developed end stage liver failure, was referred to us after having undergone resection of the entire aganglionic bowel leaving only 30 cm of proximal small intestine ending as jejunostomy. Moreover, all 18 (90%) survivors had normal serum bilirubin without signs of IFALD at median age of 14 years (Table 4). All survivors received cycled enteral antibiotics prior to ITx in order to treat symptoms of bacterial overgrowth such as abdominal bloating, diarrhea associated with worsening intolerance of enteral feeding or to prevent recurrent sepsis episodes [2,6,11,20,24]. Dilated small intestinal segment proved to be a source of bacterial overgrowth in two patients with extensive aganglionosis. Dilated segments were successfully treated by simple tapering, instead of serial transverse enteroplasty routinely used in SBS [21], to avoid
Growth, nutrition and liver function variables during and after weaning off PN at last follow-up (median age 13.9 years).
Variable
On PN (n = 7)
Weaned off PN (n = 10)
Reference
Height z score Weight z score Serum cholesterol, mmol/l Serum albumin, g/l Serum vitamin A, μmol/l Serum vitamin E, μmol/l Serum bilirubin, μmol/l Serum ALT, U/l
− 0.3 (− 0.5 to 0.1) 0 (− 0.5 to 1.0) 2.4 (2.0 to 3.0) 33 (32 to 35) 1.2 (0.7 to 1.3) 19 (17 to 26) 3 (2 to 4) 37 (17 to 64)
− 2.0 (− 2.0 to 0.9) ⁎ − 0.8 (− 1.0 to 0.0) 2.6 (2.2 to 2.8) 38 (30 to 40) 1.8 (1.4 to 2.0) ⁎ 24 (12 to 28) 6 (5 to 9) ⁎ 35 (31 to 46)
0 0 2.5–5.0 37–51 1–3 12–40 b 20 b 40
Data are median (IQR); ALT, alanine aminotransferase; PN, parenteral nutrition. ⁎ P b 0.05 between during and after weaning off PN.
338 postoperative functional obstruction of the dysmotile bowel. Antimicrobial treatment of bacterial overgrowth should be carefully pondered because of risk of multiresistant bacterial strains. Unfortunately, it is often required because of frequent episodes of bacterial overgrowth in CIPO and associated enterocolitis in patients with HD. Probability of remaining on PN at 5 years was 70% without differences between patients with CIPO or extensive aganglionosis (Fig. 1 and Table 3). This is strikingly higher than the respective figure of 19% in SBS patients treated at the same time period, confirming that children with motility disorders are less likely to wean off PN than those with SBS [21]. Comparable findings have been reported for adult CIPO patients [11]. Not surprisingly, in patients with extensive aganglionosis length of the remaining small intestine was a significant determinant of PN duration. According to previous reports none of the patients with panintestinal aganglionosis weaned off PN without ITx [13]. Overall survival was 90%, 8 of 8 in CIPO and 10 of 12 among patients with extended aganglionosis comparing well with previous reports. In CIPO, mortality rates of 10–32% before reaching adulthood have been reported with overall PN-dependency of 62–74% [4–6]. Extension of aganglionosis strongly modifies mortality in HD being up to 66% in patients with total intestinal aganglionosis [8–10]. In our material, ITx granted extended survival with benefit of cessation of PN for two patients, and after completion of this study one additional CIPO patient has been successfully transplanted. In conclusion, in our experience most of the children with severe intestinal motility disorders remain PN-dependent, while a proportion of them develop PN failure necessitating ITx. Surgical care of these patients entails a critical approach with careful planning of each procedure while strictly avoiding unnecessary ones. Long-term survival, a low incidence of IFALD and acceptable growth and nutrition are achievable with modern medical and surgical care including ITx in this group of children.
References [1] Goulet O, Ruemmele F. Causes and management of intestinal failure. Gastroenterology 2006;130:S16-28. [2] Di Lorenzo C, Youssef NN. Diagnosis and management of intestinal motility disorders. Semin Pediatr Surg 2010;19:50-8. [3] Antonucci A, Fronzoni L, Cogliandro L, et al. Chronic intestinal pseudo-obstruction. World J Gastroenterol 2008;21:2953-61. [4] Mousa H, Hyman PE, Cocjin J, et al. Long-term outcome of congenital intestinal pseudoobstruction. Dig Dis Sci 2002;47:2298-305. [5] Heneyke S, Smith VV, Spitz L, et al. Chronic intestinal pseudoobstruction: treatment and long-term follow up of 44 patients. Arch Dis Child 1999;81:21-7.
M.P. Pakarinen et al. [6] Faure C, Goulet O, Ategbo S, et al. Chronic intestinal pseudoobstruction syndrome. Clinical analysis, outcome, and prognosis in 105 children. Dig Dis Sci 1999;44:953-9. [7] Vargas JH, Sachs P, Ament ME. Chronic intestinal pseudo-obstruction syndrome in pediatrics. Results of a national survey by members of the North American Society of Pediatric gastroenterology and Nutrition. Journal Pediatr Gastroenterol Nutr 1988;7:323-32. [8] Ruttenstock E, Puri P. A meta-analysis of clinical outcome in patients with total intestinal aganglionosis. Pediatr Surg Int 2009;25:833-9. [9] Kimura O, Ono S, Furukawa T, et al. Management strategies for infants with total intestinal aganglionosis. J Pediatr Surg 2009;44:1564-7. [10] Saxton ML, Ein SH, Hoehner J, et al. Near-total intestinal aganglionosis: long-term follow-up of a morbid condition. J Pediatr Surg 2000;35:669-72. [11] Amiot A, Joly F, Alves A, et al. Long-term outcome of chronic intestinal pseudo-obstruction adult patients requiring home parenteral nutrition. Am J Gastroenterol 2009;104:1262-70. [12] Panganamamula KV, Parkman HP. Chronic intestinal pseudoobstruction. Curr Treat Options Gastroenterol 2005;8:3-11. [13] Sauvat F, Grimaldi C, Lacaille F, et al. Intestinal transplantation for total intestinal aganglionosis: a series of 12 consecutive children. J Pediatr Surg 2008;43:1833-8. [14] Loinaz C, Rodriquez MM, Kato T, et al. Intestinal and multivisceral transplantation in children with severe gastrointestinal dysmotility. J Pediatr Surg 2005;40:1598-604. [15] Bond GJ, Reyes JD. Intestinal transplantation for total/near-total aganglionosis and intestinal pseudo-obstruction. Semin Pediatr Surg 2004;13:286-92. [16] Struijs M-C, Diamond IR, de Silva N, et al. Establishing norms for intestinal length in children. J Pediatr Surg 2009:933-8. [17] Mitchell JE, Breuer RI, Zuckerman L, et al. The colon influences ileal resection diarrhea. Dig Dis Sci 1980;25:33-41. [18] Kurvinen A, Nissinen MJ, Andersson S, et al. Parenteral plant sterols and intestinal failure-associated liver disease in neonates: a prospective nationwide study. J Pediatr Gastroenterol Nutr 2012;54:803-11. [19] Kurvinen A, Nissinen MJ, Gylling H, et al. Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure. J Pediatr Gastroenterol Nutr 2011;53:440-6. [20] Quigley EM, Quera R. Small intestinal bacterial overgrowth: roles of antibiotics, prebiotics, and probiotics. Gastroenterology 2006;130: S78-90. [21] Pakarinen MP, Koivusalo AI, Rintala RJ. Outcomes of intestinal failure—a comparison between children with short bowel and dysmotile intestine. J Pediatr Surg 2009;44:2139-44. [22] Ziegler MM, Royal RE, Brandt J, et al. Extended myectomymyotomy. A therapeutic alternative for total intestinal aganglionosis. Ann Surg 1993;218:504-11. [23] Pakarinen MP, Kurvinen A, Gylling H, et al. Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition. Dig Liver Dis 2010;42:554-9. [24] Dobson R, McGuckin C, Walker G, et al. Cycled enteral antibiotics reduce sepsis rates in pediatric patients on long-term parenteral nutrition for intetinal failure. Aliment Pharmacol Ther 2011;34:1005-11. [25] Escobar MA, Grosfeld JL, West KW, et al. Long-term outcomes in total colonic aganglionosis: a 32-year experience. J Pediatr Surg 2005;40:955-61. [26] Wildhaber BE, Teitelbaum DH, Coran AG. Total colonic Hirschsprung's disease: A 28-year experience. J Pediatr Surg 2005;40:203-7. [27] Menezes M, Pini Prato A, Jasonni V, et al. Long-term clinical outcome in patients with total colonic aganglionosis: a 31-year review. J Pediatr Surg 2008;43:1696-9.