Journal of Pediatric Surgery 50 (2015) 289–292

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Intestinal Rehabilitation of Infantile Onset Very Short Bowel Syndrome Mikko P. Pakarinen a,b,⁎, Niklas Pakkasjärvi a,b, Laura Merras-Salmio b,c, Antti Koivusalo a, Risto Rintala a a b c

Section of Pediatric Surgery, Children's Hospital, University of Helsinki, Finland Pediatric Liver and Gut Research Group, Children's Hospital, University of Helsinki, Finland Section of Pediatric Gastroenterology, Children's Hospital, University of Helsinki, Finland

a r t i c l e

i n f o

Article history: Received 25 October 2014 Accepted 2 November 2014 Key words: Adaptation Autologous intestinal reconstruction Bowel lengthening Neonatal

a b s t r a c t Aim: The aim of this study was to evaluate treatment and outcomes of infantile very short bowel syndrome (SBS). Methods: A retrospective review of 42 consecutive children treated for infantile onset SBS defined as remaining small bowel length less than 30% of predicted or more than 3 months of parenteral nutrition (PN) was performed. Surgical treatment and outcomes were compared between very SBS (VSBS, small bowel length less than 25 cm, n = 12) and SBS (more than 25 cm, n = 30). Main results: Median follow-up was 5.7 years (IQR, 2.8 to 11). Absolute initial small bowel length (cm), presence of ileocecal valve (%), and proportion of remaining colon (%) was 15 (10 to 21) vs. 48 (32 to 60) (P b 0.0001), 58 vs. 50 (P = 0.74), and 95 (76 to 100) vs. 78 (60 to 100) (P = 0.27) in VSBS and SBS, respectively. More autologous intestinal reconstruction procedures per patient were performed in SBS group (27/30 vs. 5/12; P = 0.002) leading to intestinal autonomy in 2 of 4 VSBS patients in relation to 9 of 11 SBS patients (P = 0.52). Cumulative 5-year probability of weaning from PN was 46% (95% CI, 16 to 77) in VSBS and 92% (95% CI, 81 to 100) in SBS (P b 0.01). Five-year cumulative survival was 80% (95% CI, 54 to 100) in VSBS and 93% (95% CI, 83 to 100) in SBS (P N 0.30). No patients were transplanted. At final follow-up, plasma alanine aminotransferase (29 U/L [21 to 47]), bilirubin (6.0 μmol/L [3.0 to 8.0]), height (−1.4 SD [−2.5 to 0.1]), and relative weight (−5% [−12 to −2]) were similar between the groups. Conclusion: Although survival, well-preserved biochemical liver function, and growth in VSBS patients are comparable to their counterparts with longer remaining bowel, regaining intestinal autonomy remains challenging in children with the shortest small intestinal remnant. © 2015 Elsevier Inc. All rights reserved.

Short bowel syndrome (SBS) is characterized by reduced enterocyte mass, leading to failure of the intestine to provide sufficient fluid and energy absorption to meet the body’s demands [1]. Intestinal failure is most often caused by SBS as a result of massive small intestinal resection [2]. The management of intestinal failure relies on parenteral nutrition (PN) to maintain adequate growth, hydration and nutritional status [3]. Prolonged PN predisposes to increased morbidity and mortality because of associated complications, such as central line–derived blood stream infections and cholestatic liver disease [2,3]. Weaning from PN is the single most important positive prognostic factor in SBS, and is mainly predicted by remaining small bowel length [1,4,5]. Recent developments in multidisciplinary intestinal rehabilitation with application of hepatoprotective PN, efficient infection control and autologous intestinal reconstruction (AIR) surgery to optimize function of the remaining bowel together with intestinal transplantation have improved overall outlook of pediatric SBS [3]. However, it is unclear how these improvements in management modalities have influenced outcomes of the infants with the shortest remaining small intestine. To this end, we have here analyzed intestinal rehabilitation outcomes ⁎ Corresponding author at: Department of Pediatric Surgery, Children’s Hospital, University of Helsinki, PL 281, 00029 HUS, Helsinki, Finland. Tel.: +358 50 4272981. E-mail address: mikko.pakarinen@hus.fi (M.P. Pakarinen). http://dx.doi.org/10.1016/j.jpedsurg.2014.11.018 0022-3468/© 2015 Elsevier Inc. All rights reserved.

of infantile onset SBS. All consecutive infants who had undergone greater than 70% small intestinal resection or who required PN for longer than 3 months without a primary intestinal motility disorder were included. 1. Patients and methods 1.1. Study design Helsinki University Children’s Hospital is a nationwide referral center for intestinal failure and has run the only intestinal transplantation program in the country since 2009 [6]. Prospectively collected database and medical records of all children treated for intestinal failure during 1988 to 2013 in our institution were retrospectively reviewed. From this group (n = 79), children with infantile onset SBS with the initial remaining small bowel length less than 30% of predicted or duration of PN more than 3 months were included. This cohort was subdivided based on absolute bowel length into 2 groups with (i) less than or equal to 25 cm or (ii) greater than 25 cm remaining viable small intestine. Patients with a primary intestinal motility disorder were excluded [6]. Collected data consisted of gestational age and birth weight, etiology of SBS, type and time of surgical procedures, anatomy of the remaining bowel, nutritional history, dependence of PN and survival. Growth

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indexes and plasma levels of alanine aminotransferase (ALT) and bilirubin were measured at last follow-up. Growth data are expressed as height z score (SD) and height-adjusted weight (%) based on age- and sex-specific reference values of the Finnish population. Relative height-adjusted weight expresses percentage deviation from the population-based reference value. Percentage of age-adjusted predicted small bowel length was assessed based on available reference values and proportion of remaining colon as described previously [7,8]. Long-term outcomes of AIR surgery in 10 of these patients have been published previously [8]. 1.2. Principles of medical treatment Composition, volume and weekly number of cyclic nocturnal PN infusions were adjusted according to individual needs based on weight gain, growth and hydration status aiming at energy provision of 80 to 90 kcal/kg/day [6,8]. Always less than 30% of parenteral calories were provided as olive oil–based fat aiming at 1 g/kg/day. When increased risk (anticipated prolonged PN or infections) or biochemical signs of liver dysfunction were observed, lipid administration was further reduced by increasing proportion of lipid-free days. During the recent years olive oil–based PN lipid preparation was combined with fish oil and antimicrobial central venous line locks were employed [9]. By reducing the number of weekly infusions proportionally to increasing enteral intake the amount of PN was gradually tapered. Breast milk was initially used for enteral feeding and combined with lactose-free hydrolyzed iso-osmolar preparations when needed. Enteral formula was gradually changed to a more energy-dense low-osmolar whole protein preparation and solid feeds were initiated at the age 6 months to improve eating skills and adaptation. Percutaneous endoscopic feeding gastrostomies were used liberally, but continuous tube feeding was restricted during nights only if progression with preferred oral bolus feeding failed. To control high-volume intestinal excretions proton pump inhibitors and enteral sodium supplementation were used routinely. 1.3. Surgical management Surgical management of SBS aimed at rapid reestablishment of intestinal continuity [8]. Longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP) were performed as described in detail previously [8,10,11]. Depending on a child’s age, small bowel diameter above 4 to 5 cm was considered suitable for bowel lengthening. Simple tapering was performed with a linear stapler parallel to the long axis of the dilated small bowel segment when remaining bowel length was not critical. Enteric fistulas and strictures were dealt according to general surgical principles. The main indication for AIR surgery consisted of small bowel dilatation with or without obstruction in contrast examination and simultaneous symptoms of bacterial overgrowth including worsening tolerance of enteral feeds and increased intestinal secretions or D-lactate acidosis. 1.4. Ethics The hospital’s ethical committee approved this study. 1.5. Statistical analyses Unless otherwise stated, data are presented as median and interquartile range (IQR). The Mann–Whitney U test was used to compare continuous variables, and the Fisher’s Exact test for frequencies between groups. The Kaplan–Meier method with Mantel–Cox log-rank test was utilized in evaluation of cumulative risks of remaining on PN and survival. Duration of PN was calculated from the date of PN start to end of follow-up, cessation of PN, or death. Survival time extended from birth to the end of follow-up or death. Statistical significance was considered with P b 0.05.

2. Results 2.1. Patient characteristics Altogether 42 patients fulfilled the inclusion criteria, including 12 VSBS and 30 SBS patients. The groups were comparable in terms of birth weight, gestational age, underlying etiology of SBS, and followup time (Table 1). Onset of SBS occurred during the neonatal period, except for 3 SBS patients, who underwent bowel resection leading to SBS later on during the first year of life. No cases were lost to follow-up. Individual data on VSBS patients are shown in Table 2. In VSBS group median absolute and percentage of predicted initial remaining small bowel length was 15 cm (range, 7 to 25) and 11% (range, 3 to 29), respectively. The respective figures were 48 cm (range, 30 to 123) and 23% (range, 15 to 91) in SBS group (P b 0.0001 for both). No statistically significant differences between groups were observed for percentage of patients with preserved ileocecal valve and jejunoileocolic continuity or proportion of remaining colon (Table 3). 2.2. AIR surgery As shown in Table 3, the percentage of patients who received AIR surgery was identical within the groups: 4/12 and 12/30 (P = 0.74). However, when all AIR operations in addition to bowel lengthening (STEP and LILT), such as tapering, resection of dilated small bowel segment, closure of enteric fistula and stricture removal were included, the overall frequency of AIR procedures per patient was significantly higher in SBS group (27/30 vs. 5/12; P = 0.002). The median age at the first AIR surgery was 27 months (12 to 61) in VSBS group and 13 months (11 to 41) in SBS group (P = 0.76). Four VSBS children underwent 5 AIR procedures (Table 2), whereas 11 SBS children underwent 1 to 5 separate procedures in 1 to 4 different operations. AIR reoperations were performed in 1 VSBS child and in 3 SBS children (P N 0.99). The 1 VSBS child underwent reSTEP for bowel redilatation after 11 months. Three SBS patients were reoperated. Of them, 1 underwent resection of anastomotic stricture and associated segmental bowel redilatation 17 years after the initial tapering enteroplasty, 1 underwent 2 STEPs and tapering enteroplasty owing to bowel redilatation 8 and 10 years after the initial tapering, and 1 underwent tapering enteroplasty 2 years after 2 STEPs performed in a referring hospital. 2.3. Parenteral nutrition dependence and survival The overall duration of PN was 2.5 years (1.1 to 7.1) in VSBS and 0.8 years (0.4 to 1.2) in SBS group (P b 0.01). In total, 50% (6/12) of VSBS children weaned from PN after median of 1.5 years (range, 0.3 to 10) (Table 2), whereas 90% (27/30; P b 0.01) of SBS children weaned from PN after median of 0.8 years (0.4 to 1.0) (P = 0.15). Two of the 4 VSBS patients who received AIR surgery weaned off PN in comparison to 9 of 11 in SBS group (P = 0.52). Within VSBS group the median absolute length of the remaining small bowel was 19 cm (15 to 25) among the Table 1 Characteristics of short bowel patients. Variable

VSBS

SBS controls

Number Birth weight (kg) Gestational age (w) Etiology of SBS NEC Volvulus Atresia Gastroschisis Follow-up time (y)

12 1.2 (0.7–3.3) 30 (27–36)

30 2.2 (0.9–3.5) 35 (28–37)

5 (42) 3 (25) 2 (17) 2 (17) 6.9 (2.3–11)

14 (47) 7 (23) 5 (17) 4 (13) 4.7 (3.2–11)

Data are median (interquartile range) or frequency (percentage). NEC, necrotizing enterocolitis; VSBS, very short bowel syndrome. P N 0.05 for all comparisons between groups.

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Table 2 Individual demographic data, initial intestinal anatomy, operations, survival and final PN status of VSBS patients. Case

Age (y)

Gestational age (w)

Etiology

Small bowel length (cm)

Intestinal circuit

ICV

Remaining colon (%)

AIR procedures

Alive

PN duration (y)

Weaned off PN

Weekly PN infusions

1 2 3 4 5 6 7 8 9 10 11 12

17 16 11 1.3 12 3.2 7.7 6.5 7.3 2.3 2.2 1.1

26 35 36 34 27 39 38 30 27 24 29 24

NEC Atresia Atresia Gastroschisis, atresia NEC Midgut volvulus Midgut volvulus Midgut volvulus Gastroschisis, atresia NEC NEC, volvulus NEC

15 15 15 10 10 7⁎ 10⁎ 12⁎ 25 22 25 20

JIC JIC JC JIC JC JIC JIC JC JC JIC JIC JC

y y n y n y y n n y y n

100 100 80 100 61 100 100 72 90 86 100 71

STEP LILT STEP STEPx2 -

y y y n⁎⁎ y n⁎⁎ y y y y y y

0.3 16 10 1.3 3.1 3.2 7.7 6.5 2.0 1.0 0.7 1.1

y n y n y n n n y y y n

0 2 0 7 0 7 6 3 0 0 0 3

PN, parenteral nutrition; VSBS, very short bowel syndrome; NEC, necrotizing enterocolitis; JC, jejunocolic; JIC, jejunoileocolic; ICV, ileocecal valve; AIR, autologous intestinal reconstruction; STEP, serial transverse enteroplasty; LILT, longitudinal intestinal lengthening and tailoring. ⁎ Postpyloric length. ⁎⁎ Age and PN data at time of death.

weaned patients, and 11 cm (10 to 15) in those who remained PN dependent (P = 0.07). The gestational age of unadapted VSBS children was 35 weeks (30 to 38) in comparison to 27 weeks (26 to 29) among adapted VSBS children (P = 0.13). As shown in Fig. 1, cumulative risk for remaining on PN was significantly higher in VSBS group. Cumulative 2- and 5-year probability of weaning from PN was 36% (95% CI, 8 to 66) and 46% (95% CI, 16 to 77) in VSBS group and 80% (95% CI 74 to 94) and 92% (95% CI, 81 to 100) in SBS group, respectively. The 4 unadapted VSBS survivors received median of 3 weekly PN infusions at last followup (Table 2). Respective overall and 5-year cumulative survival was 83% and 80% (95% CI, 54 to 100) in VSBS and 93% and 93% (95% CI, 83 to 100) in SBS (P N 0.30 for both). Survival curves plateaued thereafter because no further deaths occurred after the first 3 years in either group (Fig. 2). Two VSBS patients born in 2000 and 2005 died of liver failure before intestinal transplantation was available. Their underlying diagnoses were gastroschisis combined with multiple intestinal atresia and midgut volvulus with 10 and 7 cm remaining small bowel, respectively (Table 2). None of the children in either group were transplanted. 2.4. Growth and liver function At the last follow-up plasma ALT values were mostly in the normal range and similar between the groups (Table 4). None of the patients were jaundiced having normal bilirubin levels excluding 1 patient with extrahepatic portal vein occlusion and splenorenal shunt, whose Table 3 Details of residual bowel anatomy and reconstructive autologous intestinal surgical procedures. Variable Small bowel length Absolute (cm) Percentage of predicted (%) Ileocecal valve present (%) Remaining colon (%) Jejunoileocolic continuity AIR-surgery patients Individual AIR procedures STEP LILT Tapering Resection of dilated segment Fistula closure Stricture alleviation

VSBS

SBS controls

15 (10–21) 11 (8–16) 7 (58) 95 (76–100) 7 (58) 4 (33)

48 (32–60) ⁎ 23 (21–32) ⁎ 15 (50) 78 (60–100) 16 (53) 12 (40)

4 1

8 1 6 2 2 8

Data are median (interquartile range) or frequency (percentage). AIR, autologous intestinal reconstruction; STEP, serial enteroplasty; LILT, longitudinal lengthening and tailoring; VSBS, very short bowel syndrome. ⁎ P b 0.0001 compared to VSBS patients.

bilirubin was 28 μmol/L. The degree of growth impairment was comparable between the groups (Table 4). 3. Discussion We have addressed single-center outcomes of infantile onset surgical SBS. The strengths of our study include a single-center setup and complete long-term follow-up. The major findings of this study suggest that long-term survival, satisfactory growth and well-preserved biochemical liver function similar to patients with longer bowel remnant are achievable also among the SBS children with the shortest remaining small intestine. However, patients with an extremely short small bowel remnant may be less often amenable to different AIR procedures, leaving around half of them dependent on PN for prolonged period of time or permanently, whereas virtually all children with longer small intestinal remnant can be weaned successfully. Recently, Infantino and co-workers presented their rehabilitation results of 28 children younger than 2 years with an average of 13 cm small bowel remaining [12]. In their study 48% of survivors adapted after median of 21 months on PN, whereas 52% underwent bowel lengthening procedures. Respective findings were very similar in the present series: 50% of VSBS children with a mean small bowel length of 15.5 cm weaned off PN after median of 18 months, whereas 33% underwent bowel lengthening. In both studies, frequency of bowel lengthening was similar in adapted and unadapted patients [12]. When remaining small bowel length decreases below 10 cm, weaning off PN is exceptional despite modern multidisciplinary approach [13,14]. Length of the remaining small bowel may be the most crucial prognostic factor for successful weaning from PN with or without bowel

Fig. 1. Cumulative risk of remaining on parenteral nutrition.

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M.P. Pakarinen et al. / Journal of Pediatric Surgery 50 (2015) 289–292 Table 4 Final growth indexes and liver function. Variable

VSBS

SBS controls

ALT (U/L) Bilirubin (μmol/L) Height (SD) Weight (%)⁎

38 (27–47) 3.5 (2.0–6.0) −1.9 (−3.3 to −1.3) −7.0 (−17 to 2.0)

29 (19–46) 6.5 (3.5–10) −1.2 (−2.3 to 0.3) −4.5 (−12 to 0.5)

Data are median (interquartile range). ALT, alanine aminotransferase; VSBS, very short bowel syndrome. P N 0.05 for all comparisons between groups. ⁎ Percentage deviation of height-adjusted weight from the reference value.

Fig. 2. Probability of survival.

lengthening surgery [1,4,5,15]. In our material, children within VSBS group who weaned had a median of 8 cm longer small bowel remnant, just failing to reach statistical significance despite the limited number of patients. Growing significance of preserved ileocecal valve and colon for achieving intestinal autonomy has been clearly demonstrated when the length of the remaining small bowel decreases below 20 cm [12]. Theoretically, prematurity and associated intestinal growth potential could improve a patient’s possibility to wean off PN. However, no such relationship was observed here among VSBS patients similarly to a previous report [12]. Although VSBS patients and their SBS controls with a longer bowel remnant had similar base line characteristics, including distribution of underlying etiologies, overall frequency of AIR procedures was significantly lower in VSBS group. This finding partly reflects the fact that in order to preserve all available mucosal absorptive surface, only bowel lengthening procedures are feasible among the patients with the shortest remnant. However, bowel lengthening in a patient with few centimetres of undilated proximal small bowel is often impossible with current techniques. Here, AIR surgery was strictly restricted to symptomatic patients with spontaneous bowel dilatation reflected by relatively high patient age at the first surgery. Whether controlled induction of dilatation followed by bowel lengthening will improve achievement of intestinal autonomy among those with the shortest remaining small bowel remains to be clarified [16,17]. Final growth indexes after a median follow-up of almost 6 years were satisfactory and not statistically different between VSBS and SBS patients, confirming adequate nutrient provision either enterally or parenterally. Comparable growth results have been reported previously [12,13]. None of the survivors either in VSBS or SBS group were cholestatic, whereas 75% of them displayed ALT value below 47 U/L (Table 4). Despite well-preserved liver biochemistry, these children require continuing surveillance of their liver function because of persistent histological liver damage [18]. Besides the 2 VSBS children who developed liver failure before refinement of our parenteral lipid administration protocol or availability of intestinal transplantation, none of the survivors of this study are currently considered as candidates for intestinal or liver transplantation. All unadapted SBS children are stable on PN without advanced liver disease and most of them are likely to wean off PN in the future. In contrast, we have performed intestinal transplantation to 5 patients with severe intestinal dysmotility and PN failure [6]. Our cumulative 5-year (and beyond) survival was 80% among VSBS patients,

being comparable to patients with longer small bowel remnant. These figures are likely to further improve in the future with increasingly efficient prevention of intestinal failure–associated liver disease and septic complications. Others have reported roughly similar survival rates even in more severe SBS [13]. Main limitations of this study include relatively low number of these rare patients and retrospective study design, not allowing critical assessment of the true effect of AIR surgery on weaning and introducing some inherent variations in patient management overtime. However, we believe that findings of this report help to delineate challenges in treatment of SBS children with the shortest small bowel remnant and further improve their outcomes. References [1] Goulet O, Ruemmele F, Lacaille F, et al. Irreversible intestinal failure. J Pediatr Gastroenterol Nutr 2004;38:250–69. [2] Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: Initial report from the pediatric intestinal failure consortium. J Pediatr 2012;161:723–8. [3] D’Antiga L, Goulet O. Intestinal failure in children: The European view. J Pediatr Gastroenterol Nutr 2013;56:118–26. [4] Fallon EM, Mitchell PD, Nehra D, et al. Neonates with short bowel syndrome. JAMA Surg 2014. http://dx.doi.org/10.1001/jamasurg.2013.4332 [Epub ahead of print]. [5] Spencer A, Neaga A, West B, et al. Pediatric short bowel syndrome – redefining predictors of success. Ann Surg 2005;242:403–12. [6] Pakarinen MP, Kurvinen A, Koivusalo AI, et al. Surgical treatment and outcomes of severe pediatric intestinal motility disorders requiring parenteral nutrition. J Pediatr Surg 2013;48:333–8. [7] Struijs MC, Diamond IR, de Silva N, et al. Establishing norms for intestinal length in children. J Pediatr Surg 2009;44:933–8. [8] Pakarinen MP, Kurvinen A, Koivusalo AI, et al. Long-term controlled outcomes after autologous intestinal reconstruction surgery in treatment of severe short bowel syndrome. J Pediatr Surg 2013;48:339–44. [9] Kurvinen A, Nissinen MJ, Andersson S, et al. Parenteral plant sterols and intestinal failure associated liver disease in neonates. J Pediatr Gastroenterol Nutr 2012;54:803–11. [10] Bianchi A. Intestinal loop lengthening-a technique for increasing small intestine length. J Pediatr Surg 1980;15:145–51. [11] Kim HB, Fauza D, Garza J, et al. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure. J Pediatr Surg 2003;38:425–9. [12] Infantino B, Mercer D, Jobson B, et al. Successful rehabilitation in pediatric ultrashort small bowel syndrome. J Pediatr 2013;163:1361–6. [13] Diamanti A, Conforti A, Panetta F, et al. Long-Term outcome of home parenteral nutrition in patients with ultra-short bowel syndrome. J Pediatr Gastroenterol Nutr 2014;58:438–42. [14] Sanchez SE, Javid PJ, Healey PJ, et al. Ultrashort bowel syndrome in children. J Pediatr Gastroenterol Nutr 2013;56:36–9. [15] Sudan D, Thompson J, Botha J, et al. Comparison of intestinal lengthening procedures for patients with short bowel syndrome. Ann Surg 2007;246:593–604. [16] Wales PW, Jancelewicz T, Romao RL. Delayed primary serial transverse enteroplasty as a novel management strategy for infants with congenital ultra-short bowel. J Pediatr Surg 2013;48:993–9. [17] Murphy F, Khalil BA, Gozzini S, et al. Controlled tissue expansion in the initial management of the short bowel state. World J Surg 2011;35:1142–5. [18] Mutanen A, Lohi J, Heikkilä P, et al. Persistent abnormal liver fibrosis after weaning off parenteral nutrition in pediatric intestinal failure. Hepatology 2013;58:729–38.

Intestinal rehabilitation of infantile onset very short bowel syndrome.

The aim of this study was to evaluate treatment and outcomes of infantile very short bowel syndrome (SBS)...
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