Nikhil Pai, MD CNSC FAAP FRCPC Associate Professor, Pediatric GI & Nutrition,

McMaster UniversityMedical Lead, Complex Pediatric Nutrition Service

McMaster Children’s Hospital

The Evolving Management of Pediatric

Intestinal Failure

Disclosures

Nutricia, Ferring, Takeda Takeda

ADVISORY BOARDS SPEAKER FEES

Our first talk of today’s session will focus on the management of pediatric intestinal failure (IF) patients.

Common presentations of early onset intestinal failure and principles + pearls of management.

Prognostic factors in intestinal failure patients, and key considerations for long-term monitoring.

GLP-2 AGONISTS

Early experience with the role of GLP-2 agonists in management, including evolving principles of patient selection.

MANAGEMENT

OUTCOMES

Definitions are important in pediatric IF, where etiology isn’t always obvious.● Intestinal failure: gastrointestinal function

is inadequate to maintain nutrient, growth, and hydration status.

● Short bowel syndrome (SBS): intestinal failure due to reduced small intestinal mass (surgical resection).

● Adaptation: process following intestinal resection where remaining bowel undergoes morphologic and functional changes to increase absorptive capacity.

Warner BW. The Pathogenesis of Resection-Associated Intestinal Adaptation. Cell Mol Gastroenterol Hepatol. 2016;2(4):429-438. Published 2016 May 14. doi:10.1016/j.jcmgh.2016.05.001

18%

Pediatric IF occurs in approximately 2% of all neonatal intensive care unit admissions; 80% of all cases develop during the neonatal period

26%

May have full intestinal length16%

10%

Congenital enteropathies, intestinal pseudoobstruction, etc.

Often due to malrotation9%

21%

NEC

GASTROSCHISIS

VOLVULUS

INTESTINAL ATRESIA

OTHER DIAGNOSES

TRAUMA, CROHN’S, MALIGNANCY

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(4):723-8.e2. doi:10.1016/j.jpeds.2012.03.062

Strong association with prematurity

Syndromic or isolated

Several general principles that must be routinely addressed in all patients at each visit.

Adjusting Nutrition for

GrowthIdeal growth curves, Bolus

feeding

Prevention of PN associated liver

disease (PNALD)*Next slide

Renal Function, Metabolic Bone

Disease, Neurocognitive Development

Initiation of Enteral Feeds

Rapid advancement, oral feeding

ONE

FOUR

THREE FIVE

TWOPsychosocial,

Financial Burdens

Newer TPN lipid formulations have reduced previously high rates of PNALD / PNAC.

Historically present in 40-60% of childrenEffects of newer lipid formulations reduced phytosterols

TREATMENT: FOLE effective at treatment PNAC● (2021) n=262, 65% FOLE vs. 16% SOLE had resolution of

cholestasis (p<0.0001)

PREVENTION: MOLE may prevent PNAC● (2021) n=136, 16.4% SOLE vs. 2.5% MOLE

developed cholestasis after >2wk (p=0.007) ● (2021) n=107, 44.8% SOLE vs. 30% MOLE had

cholestasis after >2wk (RR=0.67; 95% CI: 0.39-1.15)

Gura KM, Premkumar MH, Calkins KL, Puder M. Fish Oil Emulsion Reduces Liver Injury and Liver Transplantation in Children with Intestinal Failure-Associated Liver Disease: A Multicenter Integrated Study. J Pediatr. 2021;230:46-54.e2. Jackson RL, White PZ, Zalla J. SMOFlipid vs Intralipid 20%: Effect of Mixed-Oil vs Soybean-Oil Emulsion on Parenteral Nutrition-Associated Cholestasis in the Neonatal Population. JPEN J Parenter Enteral Nutr. 2021;45(2):339-346.Ferguson CL, Perry C, Subramanian M, Gillette C, Ayers K, Welch C. Mixed Oil-Based Lipid Emulsions vs Soybean Oil-Based Lipid Emulsions on Incidence and Severity of Intestinal Failure-Associated Liver Disease in a Neonatal Intensive Care Unit. JPEN J ParenterEnteral Nutr. 2021;45(2):303-308.

Nutritional management is essential to support growth and maximize potential for early adaptation.

Occurs even when only small amounts of feeds are given (“trophic feeds”)

Absence of enteral feeding may induce atrophy of the mucosa

High rates of oral feeding aversion

NUTRIENTS IN THE INTESTINAL LUMEN MAY BE MOST EFFECTIVE IF ENTERAL FEEDS INITIATED EARLY

Maximize enteral feeding early (program-specific “schedules”)

Serial measurements of weight, length used to guide targets

REE is similar to healthy controls, +30-70% from enteral vs. PN feeding

Transition to intermittent bolus feedings: maximize adaptation, cyclical release of intestinal hormones, polymeric formula

Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr. 2001;139(1):27-33. 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(4):723-8.e2.

Nutritional management is essential to support growth and maximize potential for early adaptation.

Occurs even when only small amounts of feeds are given (“trophic feeds”)

Absence of enteral feeding may induce atrophy of the mucosa

High rates of oral feeding aversion

NUTRIENTS IN THE INTESTINAL LUMEN MAY BE MOST EFFECTIVE IF ENTERAL FEEDS INITIATED EARLY

Maximize enteral feeding early (program-specific “schedules”)

Serial measurements of weight, length used to guide targets

REE is similar to healthy controls, +30-70% from enteral vs. PN feeding

Transition to intermittent bolus feedings: maximize adaptation, cyclical release of intestinal hormones, polymeric formula

Andorsky DJ, Lund DP, Lillehei CW, et al. Nutritional and other postoperative management of neonates with short bowel syndrome correlates with clinical outcomes. J Pediatr. 2001;139(1):27-33. 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(4):723-8.e2.

Ongoing monitoring required for short- and long-term complications.

Neurocognitive delayD-lactic acidosis

Ostomy breakdown

Psychosocial, family burdenMental health

Deficiencies of ADEK, Fe, B12EFA deficiency

Risks highest with weaning PN

Diarrhea, dysmotility Anastomotic ulcers EsophagitisPeptic ulcer diseaseSIBO

Metabolic bone disease (Vit D, Ca)

Kidney stones (calcium oxalate), increased rate of CKD

Catheter related complications: CLABSI, thrombi, occlusion, breakage

PNALDCholelithiasis

Eosinophilic diseaseAllergic disorders

Candidates for autologous intestinal rehabilitation surgeries (AIRS) + intestinal/multivisceral transplant.

TRANSPLANT LESS COMMON (26% to 5.4%, PRE/POST 2007)

Progressive PNALD

Dilated small intestine (often with complications)

Loss of vascular access (≥3 CVC sites)

Congenital enteropathies (ie. MVID, Tufting, IED, aganglionosis, etc.)

Adequate bowel lengthening predicted

Absence of underlying gastrointestinal motility disorder

Burghardt KM, Wales PW, de Silva N, et al. Pediatric intestinal transplant listing criteria - a call for a change in the new era of intestinal failure outcomes. Am J Transplant. 2015;15(6):1674-1681. doi:10.1111/ajt.13147

Two main AIRS procedures used to increase bowel length and absorptive area: STEP, and Bianchi.

● No comparative data to support its use● Improves: feed tolerance, SIBO, bowel continuity● Indications: dilatation, >1st year, sepsis, IFALD

● STEP: Serial transverse enteroplasty procedure● Bianchi procedure/LILT: Longitudinal intestinal

lengthening and tailoring (challenges: intestinal blood flow, segments of variable dilatation)

Post-STEP anastomotic bleeding concerns:● 2014 J Ped Surg: n=23 post-STEP; 13% GIB● 2021 J Ped Surg: n=16; 1 GIB required resection● Both studies: 2.75-3.14yr followup

Kim HB, Fauza D, Garza J, Oh JT, Nurko S, Jaksic T. Serial transverse enteroplasty (STEP): a novel bowel lengthening procedure. J Pediatr Surg. 2003;38(3):425-429.Bianchi A. From the cradle to enteral autonomy: the role of autologous gastrointestinal reconstruction. Gastroenterology. 2006;130(2 Suppl 1):S138-S146. doi:10.1053/j.gastro.2005.09.070

Lemoine C, Larkin K, Brennan K, Zoller-Thompson C, Cohran V, Superina R. Repeat serial transverse enteroplasty procedure (reSTEP): Is it worth it? Journal of Pediatric Surgery, 2021. doi.org/10.1016/j.jpedsurg.2020.12.026.Fisher JG, Stamm DA, Modi BP, Duggan C, Jaksic T. Gastrointestinal bleeding as a complication of serial transverse enteroplasty. J Pediatr Surg. 2014;49(5):745-749.

GLP-2 agonists are emerging onto the Canadian pediatric market for Summer/Fall 2021.

Common presentations of early onset intestinal failure and principles + pearls of management.

Prognostic factors in intestinal failure patients, and key considerations for long-term monitoring.

GLP-2 AGONISTS

Early experience with the role of GLP-2 agonists in management, including evolving principles of patient selection.

MANAGEMENT

OUTCOMES

Role of GLP-2 Agonists in the Pathophysiology of Intestinal Failure.

SITE

TRANSIT

ENTEROCYTES

APPROVE

GLP-2 synthesized in enteroendocrine L cells

Slows intestinal transit time, increases small intestinal nutrient absorption

Administration significantly increases

villous height + SB mass

Approved for use in Canadian adults with

intestinal failure since 2019, and children in

USA/Europe since 2017

Real-world data shows promise in pediatrics.

• 12-month data• Multicentre (N=8) prospective,

observational cohort• N=17 (1-18yo)

• Average SB remnant 52cmAverage PN 55mL/kg/day

• No change in PN, surgery x 3mo• Outcome: >20% PN decrease

Ramos Boluda E, et al (Spain); JPGN Dec, 2020

Ramos Boluda, E et al. Experience With Teduglutide in Pediatric Short Bowel Syndrome: First Real-life Data, JPGN: December 2020 - Volume 71 - Issue 6 - p 734-739.

Ongoing French trial shows smaller benefits (REVE Study).

• Oral abstract (CIRTA 2019)• N=12, 5-16 years old• Average SB remnant <80 cm

Goulet et al (France); Transplant (July 2019)

Lambe, Cecile, Goulet, Olivier et al. The REVE study, preliminary results. A Monocentric Single-arm study to characterize the long-term safety, efficacy, and pharmacodynamic of GLP-2 analog (Revestive®) in the management of short bowel syndrome pediatric patients on home-

parenteral nutrition (HPN), Transplantation: July 2019 - Volume 103 - Issue 7S2 - p S11

3mo: 9/12 children, 30% PN reduction 6mo: 3/12 children, 44% PN reduction• High drop-out rate• Study is ongoing, projected

enrolment n =25

McMaster Children’s Hospital’s Intestinal Failure Team First Experience with Teduglutide.

01.

02.03.

04.

32 CLABSI episodesSeptic hip, Right atrial clotNo CVL access

SUMMER, 2020

Loss of central accessMildly elevated liver enzymes

MULTIVISCERAL TRANSPLANT LIST2 weeks = -15%, +2kg

6 weeks = -1 day PN, +2kgOctober PICC comes out: PN discontinued altogether

GLP-2 AUG, 2020

8 months laterStools 2-3 per day (Bristol 4) , intake 3000mL/day Weight 25.4kg à 30.4kgFirst bath, sleepover, formed bowel movement

APRIL, 2021 (TPN STOPPED)

12yo boy with gastroschisis, 26cm SB, TPN 7d/week2x STEP proceduresLiquid stools (5x/day, Bristol 7)Attempts to wean PN: weight loss, loperamide maximized, multiple formula changes

Key questions remain regarding patient selection for use of GLP-2 Agonists in Canadian patients.

BALANCING FACTORS

Many unanswered questions remain:- QOL- Transplant-free survival- CLABSI rates- Cost benefit analyses

LONG-TERM DATA

$300,000 per year of treatment (estimates).Data suggests return to baseline with discontinuation of treatment.

COST

Patients with loss of functional L-cell mass.

Patient vs. provider goals.

SELECTION

*Emerging dataEARLY VS. LATE INITIATION

Early vs. late use of GLP-2 agonists: is there a role for earlier initiation of therapy?

2020 JPEN: Neonatal short‐bowel piglets assigned to 7d teduglutide treatment vs saline● Hyperplasia: Villus hyperplasia occurred at

Day 7 (p=0.003), not durable after 7 days of treatment cessation (p=0.081)

● Length: Length increased at Day 7 (p=0.005), maintained at day 14 (p=<0.001)

Benefit of “spiking” existing L-cell GLP-2 secretion vs waiting for failure to progressGreatest intestinal adaptation in first 1-4yrs?

Intestinal growth may be a lasting outcome of treatment with long-acting GLP-2 analogues

Hinchliffe T, Pauline ML, Wizzard PR, Nation PN, Brubaker P, Campbell JR, Kim Y, Dimitriadou V, Wales PW, Turner JM. Durability of Linear Small-Intestinal Growth Following Treatment Discontinuation of Long-Acting Glucagon-Like Peptide 2 (GLP-2) Analogues. JPEN J Parenter Enteral Nutr. 2020 Nov 25. doi: 10.1002/jpen.2053. Epub ahead of print. PMID: 33241564.

Transitioning the pediatric patient to the adult world: Predictions and prognosis for the future.

Common presentations of early onset intestinal failure and principles + pearls of management.

Prognostic factors in intestinal failure patients, and key considerations for long-term monitoring.

GLP-2 AGONISTS

Early experience with the role of GLP-2 agonists in management, including evolving principles of patient selection.

MANAGEMENT

OUTCOMES

Longterm statistics suggest sepsis rate is the primary modifiable factor associated with mortality.

2019 Am J Clin Nut: Meta-analysis weighted by follow-up duration.

175 cohorts (9,318 patients; 34,549 years)Mortality 5.2%/yr (95% CI: 4.3, 6.0)● Sepsis● IFALD

Sepsis rate predictive of IFALDEnteral autonomy associated with SB length

Sepsis rate associated with mortality and liver failure

Enteral autonomy correlates with small-bowel length

Aureliane Chantal Stania Pierret, James Thomas Wilkinson, Matthias Zilbauer, Jake Peter Mann, Clinical outcomes in pediatric intestinal failure: a meta-analysis and meta-regression, The American Journal of Clinical Nutrition, Volume 110, Issue 2, August 2019, Pages 430–436.

Multiple extra-intestinal considerations long-term.

85%

Micronutrient Deficiencies

Metabolic Bone Disease

Cognitive Development

Long-term micronutrient deficiencies after PN weanN=30 children

12wk transition from PN to full ENDuring transition: 42% >1 micronutrient deficiency

After transition: 70% >1 micronutrient deficiencyVitamin D, iron, zinc most common

Yang CF, Duro D, Zurakowski D, Lee M, Jaksic T, Duggan C. High prevalence of multiple micronutrient deficiencies in children with intestinal failure: a longitudinal study. J Pediatr. 2011;159(1):39-44.e1. doi:10.1016/j.jpeds.2010.12.049Demehri FR, Simha S, Stephens L, et al. Pediatric intestinal failure: Predictors of metabolic bone disease. J PediatrSurg. 2015;50(6):958-962. doi:10.1016/j.jpedsurg.2015.03.018Gunnar RJ, Kanerva K, Salmi S, et al. Neonatal Intestinal Failure Is Independently Associated With Impaired Cognitive Development Later in Childhood. J Pediatr Gastroenterol Nutr. 2020;70(1):64-71. doi:10.1097/MPG.0000000000002529

Pediatric IF associated with significant risk of MBD, related to duration of PN-dependence.N=36 childrenMean BMD -1.16 ± 1.32Vitamin D <30ng/mL in 63.8%; Elevated PTH >55pg/mL in 25.0% Pathologic fractures in 11.1% PN duration predicted decreased BMD (BMD=−0.132/yr, p=0.006)

Adverse cognitive outcome associated with # of interventions under general anesthesia, length of inpatient status, prematurity2020 JPGN: N=30 childrenMedian duration PN = 13 monthsMedian IQ 78 (IQR 65–91); 35% <70 (-2SD)Significant motor impairment in 36%

85%

Stunting

Anastomotic Ulcers

Renal Disease

Frequently develop at resection, anastomosisRisk factors: tissue perfusion, IBD-like syndrome, hyperacidity, AIRS procedures all risk factors2018 J Ped Surg: 8/114 children with SBS had AU- 6/114 had AU persistence after medical Rx- 3/114 required surgical revision

Weaning from PN associated with stunting2018 JPGN: N=52, median followup 3.4 yearsBaseline Height for Age -0.96 SDCatch-up growth achieved during PNHeight for Age decreased after weaning PN (P=0.0001) Lean body mass -1.21 SD

Reduces calcium binding to oxalate, high rate of kidney stones in patientsHyperoxaluria secondary to fat malabsorptionBinding of calcium to free fatty acids in intestine

Fusaro F, Tambucci R, Romeo E, et al. Anastomotic ulcers in short bowel syndrome: New suggestions from a multidisciplinary approach. J Pediatr Surg. 2018;53(3):483-488. doi:10.1016/j.jpedsurg.2017.05.030Neelis E, Olieman J, Rizopoulos D, et al. Growth, Body Composition, and Micronutrient Abnormalities During and After Weaning Off Home Parenteral Nutrition. J Pediatr Gastroenterol Nutr. 2018;67(5):e95-e100. doi:10.1097/MPG.0000000000002090

Multiple extra-intestinal considerations long-term.

Enteral autonomy is contingent upon enteral anatomy: length of retained ileal segment most associated with early adaptation.

Enteral autonomy attributed to residual intestinal length: 96% >50cm vs. 38% <50cm

Preservation of IC Valve, ileum

Underlying diagnosis of NEC (not: gastroschisis, atresias, dysmotility syndromes)

Multidisciplinary intestinal failure team support (rehabilitation vs. transplant)

Patient age

Fallon EM, Mitchell PD, Nehra D, et al. Neonates With Short Bowel Syndrome: An Optimistic Future for Parenteral Nutrition Independence. JAMA Surg. 2014;149(7):663–670. doi:10.1001/jamasurg.2013.4332Pakarinen MP, Koivusalo AI, Rintala RJ. Outcomes of intestinal failure--a comparison between children with short bowel and dysmotile intestine. J Pediatr Surg. 2009;44(11):2139-2144. doi:10.1016/j.jpedsurg.2009.05.002

Enteral autonomy is contingent upon enteral anatomy: length of retained ileal segment most associated with early adaptation.

Enteral autonomy attributed to residual intestinal length: 96% >50cm vs. 38% <50cm

Preservation of IC Valve, ileum

Underlying diagnosis of NEC (not: gastroschisis, atresias, dysmotility syndromes)

Multidisciplinary intestinal failure team support (rehabilitation vs. transplant)

Patient age

Fallon EM, Mitchell PD, Nehra D, et al. Neonates With Short Bowel Syndrome: An Optimistic Future for Parenteral Nutrition Independence. JAMA Surg. 2014;149(7):663–670. doi:10.1001/jamasurg.2013.4332Pakarinen MP, Koivusalo AI, Rintala RJ. Outcomes of intestinal failure--a comparison between children with short bowel and dysmotile intestine. J Pediatr Surg. 2009;44(11):2139-2144. doi:10.1016/j.jpedsurg.2009.05.002

Prevention of central line complications has impact on enteral autonomy, preventing PNALD and need for intestinal transplant.Chronic ethanol lock therapy: 70% indwelling ethanol; impacts of national shortages à 4% EDTA solutionChronic antibiotic lock therapy: concerns about antibiotic resistanceInstillation of thrombolytic agents to restore patency in occlusion

Central line associated blood stream infections- shorter SB length- lower citrulline level- SIBO (OR 7.0; p=0.009)

Central line breakage, occlusion

Thrombosis

Rahhal R, Abu-El-Haija MA, Fei L, et al. Systematic Review and Meta-Analysis of the Utilization of Ethanol Locks in Pediatric Patients With Intestinal Failure. JPEN J Parenter Enteral Nutr. 2018;42(4):690-701. doi:10.1177/0148607117722753Venturini E, Montagnani C, Benni A, et al. Central-line associated bloodstream infections in a tertiary care children's University hospital: a prospective study. BMC Infect Dis. 2016;16(1):725. Published 2016 Dec 1. doi:10.1186/s12879-016-2061-6

Cole CR, Frem JC, Schmotzer B, et al. The rate of bloodstream infection is high in infants with short bowel syndrome: relationship with small bowel bacterial overgrowth, enteral feeding, and inflammatory and immune responses. J Pediatr. 2010;156(6):941-947.e1.

Intestinal failure is a team sport.

McMaster Children’s Hospital Intestinal Failure Team:Nikhil Pai, MD | Rose-Frances Clause, NP | Heather Mileski, RD |

Jillian Owens, RD | Susan Turner, SW | McMaster Adult Gastroenterology & Nutrition Service

@paiPadpain@mcmaster.ca

Extra Slides

Additional GLP-2 study data.

Kocoshis et al. JPEN (2019) Safety and Efficacy of Teduglutide: 24wk Phase III Study

Kocoshis SA, Merritt RJ, Hill S, et al. Safety and efficacy of teduglutide in pediatric patients with intestinal failure due to short bowel syndrome: a 24-week, phase III study. JPEN J Parenter Enteral Nutr 2019;44:621-31.

Prospective dosing study, n=42 pediatric patients Week 12 response (0.05 mg/kg/day): 25% reduction in PN volume52% reduction in PN kcal/kg/day

3 patients PN independence at 0.05mg/kg/d dose1 patient PN independence at 0.025mg/kg/d dose

Carter et al (2017); J Pediatr12-Week, Open-Label Pediatric Trial of Teduglutide

Prospective PHASE III trial, n=59 childrenWeek 24 response (0.05 mg/kg/day): 69.2% reduction in >20% PN volume

3 (11.5%) = PN independence (0.05mg/kg/d)2 (8.3%) = PN independence (0.025mg/kg/d)

Carter BA, Cohran VC, Cole CR, et al. Outcomes from a 12-week, open- label, multicenter clinical trial of teduglutide in pediatric short bowel syndrome. J Pediatr 2017;181:102.e5 – 11.e5.

Pictorial View of Manifestations in Intestinal Failure

patients

Duggan CP, Jaksic T. Pediatric Intestinal Failure. N Engl J Med. 2017;377(7):666-675. doi:10.1056/NEJMra1602650