Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

doi:10.1016/j.jpeds.2012.03.062

The Journal of Pediatrics

Volume 161, Issue 4, October 2012, Pages 723-728.e2

Abstract presented at Digestive Disease Week May 6-10, 2011, Chicago, IL.

https://doi.org/10.1016/j.jpeds.2012.03.062 Get rights and content

Objective

To characterize the natural history of intestinal failure (IF) among 14 pediatric centers during the intestinal transplantation era.

Study design

The Pediatric Intestinal Failure Consortium performed a retrospective analysis of clinical and outcome data for a multicenter cohort of infants with IF. Entry criteria included infants <12 months receiving parenteral nutrition (PN) for >60 continuous days. Enteral autonomy was defined as discontinuation of PN for >3 consecutive months. Values are presented as median (25th, 75th percentiles) or as number (%).

Results

272 infants with a gestational age of 34 weeks (30, 36) and birth weight of 2.1 kg (1.2, 2.7) were followed for 25.7 months (11.2, 40.9). Residual small bowel length in 144 patients was 41 cm (25.0, 65.5). Diagnoses were necrotizing enterocolitis (71, 26%), gastroschisis (44, 16%), atresia (27, 10%), volvulus (24, 9%), combinations of these diagnoses (46, 17%), aganglionosis (11, 4%), and other single or multiple diagnoses (48, 18%). Prescribed medications included oral antibiotics (207, 76%), H2 blockers (187, 69%), and proton pump inhibitors (156, 57%). Enteral feeding approaches varied among centers; 19% of the cohort received human milk. The cohort experienced 8.9 new catheter-related blood stream infections per 1000 catheter days. The cumulative incidences for enteral autonomy, death, and intestinal transplantation were 47%, 27%, and 26%, respectively. Enteral autonomy continued into the fifth year after study entry.

Conclusions

Children with IF endure significant mortality and morbidity. Enteral autonomy may require years to achieve. Improved medical, nutritional, and surgical management may reduce time on PN, mortality, and need for transplantation.

Section snippets

Methods

The Pediatric Intestinal Failure Consortium (PIFCon) was initiated in June, 2006 and consists of 14 sites with established multidisciplinary pediatric intestinal rehabilitation programs comprised of medical, surgical, nutritional, nursing, and other specialists. Nine sites are intestinal transplant centers.

This was a multicenter retrospective cohort study. Inclusion criteria consisted of all infants with IF who were no more than 12 months of age and had received prolonged PN as a consequence of

Results

There were 272 infants who met entry criteria (Table I). Follow-up data were collected for a median 25.7 months (11.2, 40.9). Most were male infants and most were Caucasian. One-half of the cohort initiated PN within 3 days after birth, 77% were premature, and 30% of the cohort met criteria for very low birth weight (≤1500 g). Residual small bowel length was recorded for slightly more than half of the cohort and the median small bowel length remaining was 41 cm (range 1-166 cm). At study entry,

Discussion

Infants and children with IF are at risk for myriad complications as well as death. Large societal and financial costs of this relatively small subgroup of patients underlie the importance of understanding the natural history and outcomes of IF. The rarity of the condition combined with changing care practices make single center prospective studies that are adequately powered difficult to perform.

For 272 infants with IF, the cumulative percentage who achieved enteral autonomy (with death and

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Massive intestinal loss resulting in short bowel syndrome has been linked to intestinal failure associated liver disease. Efforts to elucidate the driving force behind the observed hepatic injury have identified inflammatory mediators, alterations in the microbiome, extent of structural and functional intestinal adaptation, and toxic shifts in the bile acid pool. In the present study, we posit that ileocecal resection interrupts the delivery of these hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation, thereby shielding the liver from exposure to the aforementioned noxious stimuli.
Mice underwent sham, 50% proximal, or 50% distal small bowel resection (SBR), with or without tauroursodeoxycolic acid supplementation. Enterohepatic signaling and nonsense-mediated ribonucleic acid (RNA) decay were evaluated and correlated with hepatic injury.
When compared to 50% proximal SBR, mice that underwent ileocecal resection exhibited reduced hepatic oxidative stress and exhibited a more physiological bile acid profile with increased de novo bile acid synthesis, enhanced colonic bile acid signaling, and reduced hepatic proliferation. Distal intestinal resection promoted an adaptive response including via the nonsense-mediated RNA decay pathway to satisfactorily process injurious messenger RNA and successfully maintain homeostasis. By contrast, this adaptive response was not observed in the proximal SBR group and hepatic injury persisted.
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Short bowel syndrome (SBS) is the leading cause of chronic intestinal failure. The duration of parenteral support (PS) and the long-term micronutrient needs in children with SBS vary, based on their clinical and anatomical characteristics. Our study aimed to review the clinical course and identify high risk patient groups for prolonged PS and long-term micronutrient supplementation.
A retrospective review was conducted on electronic medical records of children with SBS and chronic intestinal failure who were enrolled in the multidisciplinary intestinal rehabilitation program at Manchester Children's Hospital, UK. Children were included in the review if they required PN for more than 60 days out of 74 consecutive days and had at least 3 years of follow-up. Statistical analysis was performed using IBM SPSS Statistics 24.0.
40 children with SBS achieved enteral autonomy (EA) and 14 remained dependent on PS after 36 months of follow up. Necrotizing enterocolitis was the most common cause for intestinal resection (38.9%) followed by gastroschisis (22.2%), malrotation with volvulus (20.4%), segmental volvulus (9.3%) and long segment Hirschsprung disease (1.9%). Those who achieved EA had significantly longer intestinal length 27.5% (15.0–39.3) than those who remained on PS 6.0% (1.5–12.5) (p < 0.001). Type I SBS was only found in the PS cohort. Median PN dependence was 10.82 months [IQR 5.73–20.78]. Congenital diagnosis was associated with longer PN dependence (21.0 ± 20.0) than acquired (8.7 ± 7.8 months), (p = 0.02). The need for micronutrient supplementation was assessed after the transition to EA; 87.5% children had at least one micronutrient depletion, most commonly Vitamin D (64.1%), followed by iron (48.7%), Vitamin B12 (34.2%), and vitamin E (28.6%). Iron deficiency and vitamin A depletion were correlated with longer PS after multivariate analysis (OR: 1.103, 1.006–1.210, p = 0.037 and OR: 1.048, 0.998–1.102, p = 0.062 respectively).
In our cohort, small bowel length was the main predictor for EA. Children on longer PS, had more often a congenital cause of resection and were at risk for micronutrient deficiencies in EA.
Cost-utility analysis of teduglutide compared to standard care in weaning parenteral nutrition support in children with short bowel syndrome
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A growing proportion of children with short bowel syndrome (SBS) remain dependent on long-term parenteral nutrition (PN). Teduglutide offers the potential for more children to decrease PN support and achieve enteral autonomy (EA), but at a significant expense. This study aims to assess the incremental costs of teduglutide plus standard of care compared to standard of care alone in weaning PN support per quality-adjusted life year (QALY) gained in children with SBS.
This is a cost-utility analysis comparing teduglutide with standard of care alone in children with SBS. A microsimulation model of children with SBS on PN aged 1–17 years was constructed over a time horizon of six years, with a cycle length of one month. The study adopted the healthcare system and societal payer perspectives in Ontario, Canada. The health outcome measure was QALYs, with results expressed in terms of incremental costs and QALYs. Scenario analyses were performed to examine the effects of different time horizons, timing of teduglutide initiation, and modeling cost of teduglutide based on pediatric weight-dosing.
Incremental healthcare system costs for teduglutide compared to standard of care were CAD$441,314 (95% CI, 414,006 to 441,314) and incremental QALYs were 1.80 (95% CI, 1.70 to 1.89) resulting in an incremental cost-effectiveness ratio (ICER) of CAD$285,334 (95% CI, 178,209 to 392,459) per QALY gained. Incremental societal costs were CAD$418,504 (95% CI, 409,487 to 427,522) and incremental societal QALYs were 1.91 (95% CI, 1.85 to 1.98) resulting in an ICER of CAD$261,880 (95% CI, 136,887 to 386,874) per QALY gained. Scenario analysis showed that teduglutide was cost-effective when it was started two years after intestinal resection (ICER CAD$48,741, 95% CI, 17,317 to 80,165) and when its monthly cost was adjusted using weight-based dosing, avoiding wastage of the remaining 5 mg dose vial (Teduglutide dominated over SOC as the less costly and most effective strategy).
Although teduglutide was not cost-effective in weaning PN support in children with SBS, starting teduglutide once natural intestinal adaptation is reduced and adjusting its monthly cost to reflect cost by volume as dictated by weight-based dosing rendered the intervention cost-effective relative to standard of care. These results indicate the potential for clinicians to re-assess optimal time for initiation of teduglutide after intestinal resection, drug manufacturers to consider the use of multi-dose or paediatric-dose vials, and the opportunity for decision-makers to re-evaluate teduglutide funding.
A nordic multicenter study on contemporary outcomes of pediatric short bowel syndrome in 208 patients
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Despite advances in the management of short bowel syndrome related intestinal failure (SBS-IF), large-scale contemporary pediatric studies are scarce. The aim of this multicenter study was to assess key outcomes and clinical prognostic factors in a recent Nordic pediatric SBS-IF population.
Patients with SBS-IF treated during 2010–2019, whose parenteral support (PS) started at age <1 year and continued >60 consecutive days were included and retrospectively reviewed. All six participating centers followed multidisciplinary SBS-IF management. Risk factors for PS dependency, intestinal failure associated liver disease (IFALD) and mortality were assessed with Cox regression and Kaplan Meier analyses. IFALD was defined with serum liver biochemistry levels.
Among 208 patients, SBS-IF resulted from NEC in 49%, gastroschisis w/wo atresia in 14%, small bowel atresia in 12%, volvulus in 11%, and other diagnoses in 14%. Median age-adjusted small bowel length was 43% (IQR 21–80%). After median follow up of 4.4 years (IQR 2.5–6.9), enteral autonomy was reached by 76%, none had undergone intestinal transplantation, and overall survival was 96%. Half of deaths (4/8) were caused by septic complications. Although biochemical cholestasis occurred only in 3% at latest follow-up and none of deaths were directly caused by IFALD, elevated liver biochemistry (HR 0.136; P = 0.017) and shorter remaining small bowel (HR 0.941; P = 0.040) predicted mortality. Shorter remaining small bowel and colon, and presence of end-ostomy were the main predictors of PS dependency, but not IFALD. Patients with NEC reached enteral autonomy more efficiently and had decreased incidence of IFALD compared to other etiologies.
Although with current multidisciplinary management, prognosis of pediatric SBS is encouraging, septic complications and IFALD still associated with the remaining low mortality rate.
Intestinal adaptation and rehabilitation
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Massive intestinal resection is a regrettably necessary but life-saving intervention for progressive or fulminant necrotizing enterocolitis (NEC). However, the resultant short bowel syndrome (SBS) poses its own array of challenges and complications. Within hours of such an abrupt loss of intestinal length, the intestine begins to adapt. Our ability to understand this process of intestinal adaptation has proven critical in our ability to clinically treat the challenging problem of short bowel syndrome. This review first highlights key data relating to intestinal adaptation including structural and functional changes, biochemical regulation, and other factors affecting the magnitude of intestinal adaptation responses. We then focus on intestinal rehabilitation as it relates to strategies to enhance intestinal adaptation while meeting nutritional needs and preventing complications of parenteral nutrition.
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Resection-associated liver steatosis, injury, and fibrosis is a devastating complication associated with massive small bowel resection (SBR). Peroxisome proliferator-activated receptor-alpha (PPARα) is a key regulator of intestinal lipid transport and metabolism whose expression is selectively increased after SBR. Here we asked if attenuating intestinal PPARα signaling would prevent steatosis and liver injury after SBR.
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: Supported by the National Institutes of Health NIDDK (grant 1 R21 DK081059-01). C.D. received funding from NICHD (K24 HD058795). The authors declare no conflicts of interest.

^∗: List of key members of the Pediatric Intestinal Failure Consortium is available at www.jpeds.com (Appendix).

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Original ArticleNatural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

Best Pract Res Clin Gastroenterol

J Pediatr

J Pediatr

J Surg Res

J Pediatr Surg

Am J Clin Nutr

J Pediatr Surg

J Pediatr

Gastroenterology

J Pediatr

J Pediatr Surg

Chem Biol

Clin Gastroenterol Hepatol

Nutrition

Irreversible intestinal failure

J Pediatr Gastroenterol Nutr

Intestinal failure and small bowel transplantation, including clinical nutrition: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition

J Pediatr Gastroenterol Nutr

Extreme short bowel syndrome in neonates: an indication for small bowel transplantation?

Transplant Proc

Short bowel syndrome: parenteral nutrition versus intestinal transplantation. Where are we today?

Dig Dis Sci

A multidisciplinary approach to the treatment of intestinal failure

J Gastrointest Surg

Original Article
Natural History of Pediatric Intestinal Failure: Initial Report from the Pediatric Intestinal Failure Consortium