Long-term outcomes of pediatric intestinal failure

Author’s Accepted Manuscript Long-term Outcomes of Pediatric Intestinal Failure Brenna S. Fullerton, Charles R. Hong, Tom Jaksic

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To appear in: Seminars in Pediatric Surgery Cite this article as: Brenna S. Fullerton, Charles R. Hong and Tom Jaksic, Longterm Outcomes of Pediatric Intestinal Failure, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2017.09.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Long-term Outcomes of Pediatric Intestinal Failure Brenna S. Fullerton1 MD, Charles R. Hong1 MD, Tom Jaksic1MD, PhD

Center for Advanced Intestinal Rehabilitation, Department of Surgery, Boston Children’s Hospital and

1

Harvard Medical School, Boston, MA

Support: Boston Children’s Hospital Chair’s Surgical Research Fellowship (Fullerton), NIH P30DK040561-17 (Jaksic)

*

Corresponding author and requests for reprints:

E-mail: [email protected] Address: 300 Longwood Avenue, Fegan 3, Boston, MA 02115 Phone: +1 617 355 9600 Fax: +1 617 730 0477

Abstract Management of pediatric intestinal failure has evolved in recent decades, with improved survival since the advent of specialized multidisciplinary intestinal failure centers. Though sepsis and intestinal failure associated liver disease still contribute to mortality, we now have growing data on the long-term outcomes for this population. While intestinal adaptation and parenteral nutrition weaning is most rapid during the first year on parenteral support, achievement of enteral autonomy is possible even after many years as energy and protein requirements decline dramatically with age. Intestinal transplant is an option for patients experiencing complications of long-term parenteral nutrition who are expected to have permanent intestinal failure, but outcomes are hindered by immunosuppression related

complications. Much of the available data comes from single center retrospective reports, with variable inclusion criteria, intestinal failure definitions, and follow-up durations; this limits the ability to analyze outcomes and identify best practices. As most children now survive long-term, the focus of management has shifted to the avoidance and management of comorbidities, support of normal growth and development, and optimization of quality of life for these medically and surgically complex patients. Keywords: intestinal failure, short bowel syndrome, long-term outcomes, parenteral nutrition, children, complications

Introduction From the first reported successful use of total parenteral nutrition (PN) in an infant in 1967 to the proliferation of multidisciplinary programs supporting children on long-term home PN, the management of intestinal failure (IF) has evolved (1-5), with improved survival rates. In this review we highlight contemporary reports of long-term outcomes for pediatric patients with severe IF, including a discussion of commonly encountered complications. All outcomes described herein must be understood within the context of the programs reporting. There are many parts of the world where the medical systems necessary to support the longterm management of these resource intensive patients are not established (6). Published data come primarily from tertiary referral centers, and thus reflect the outcomes of patients who survived their initial insult and had access to these centers. Outcomes therefore tend to represent a highly selected group, and it should be understood that they do not include the full denominator of every child with severe IF. The definition of IF, criteria for study inclusion, length of follow-up, and management algorithms vary by center. For a better understanding of the outcomes of pediatric IF, long-term prospective multi-center collaboration is required.

Intestinal failure may be due to short bowel syndrome (SBS), primary dysmotility disorders (e.g. chronic intestinal pseudoobstruction) or congenital mucosal defects (e.g. tufting enteropathy and microvillus inclusion disease). For this review we focus on SBS, which is the most common etiology of IF and the most surgically relevant. Additionally it has the greatest potential for bowel rehabilitation. Current Survival Survival rates have improved over time with multidisciplinary intestinal rehabilitation programs and hepatoprotective strategies of PN management (1-3, 5). Table 1 reflects recent published survival data in pediatric IF from a variety of single centers and a collaborative study that included 14 North American intestinal rehabilitation centers (PIFCON). Exact follow-up duration varied between studies and was not consistently reported, but all had median follow-up of at least several years. Most centers reported greater than 90% long-term survival. The common causes of death continue to be intestinal failure associated liver disease (IFALD) and sepsis from central line associated bloodstream infections (CLABSIs), both of which are reduced in coordinated intestinal rehabilitation programs (2). The achievement of enteral autonomy, which eliminates the risk of CLABSI and the hepatotoxicity of continued PN usage remains a critical predictor of long-term survival (7). Biochemical evidence of cholestatic liver disease, shorter bowel length, and nonintestinal primary disease process are other risk factors for mortality, while care at a multidisciplinary intestinal rehabilitation program is protective (1, 2, 8, 9). In a multicenter United States analysis, nonwhite race was an independent predictor of increased mortality and decreased likelihood of receiving a transplant, highlighting concerns about equitable access to resources for all children (10). Among reports from intestinal rehabilitation programs, mortality ranges from 6.4% to 37.5%, with variation perhaps attributable to differences in baseline patient populations and reporting era (9).

Enteral Autonomy The presence of central venous access for PN is a key risk factor for morbidity and mortality among patients with IF, therefore, complete weaning from PN is a central goal of intestinal rehabilitation efforts (7). Although the most rapid weaning occurs within the first year after PN initiation, patients do continue to achieve enteral autonomy after many years of PN dependence as their intestine adapts and nutritional needs decline with age (11, 12). While multiple strategies are used to promote intestinal adaptation, including gradual feeding advancement, treatment of dysmotility and bacterial overgrowth, early stoma closures, and minimization of liver disease, the most important strategy may be patience. Fluid and nutritional requirements for normal growth and development decline steeply throughout infancy and early childhood, but continue to fall gradually until the child stops growing, and beyond (Figure 1) (13). Bowel length is consistently the best predictor of likelihood of weaning from PN, although the degree of intestinal dysmotility and the absorptive capacity of the residual bowel also play important roles. In one study of neonates with SBS, defined as bowel length less than 100 cm, survivors with >50cm of residual bowel had an 88% chance of weaning from PN by 1 year of life, and a 96% chance by two years. Among survivors with <50cm of residual bowel, 23% had achieved enteral autonomy by 1 year, which increased to 38% after two years, and 71% after 4.75 years (14). With intestinal rehabilitation, enteral autonomy without transplant is even achievable for some neonates with less than 20 cm of small bowel (14-16). Other factors associated with an increased likelihood of weaning from PN include: diagnosis of necrotizing enterocolitis, higher serum citrulline, bowel in continuity, normal bowel motility, lack of intestinal dilation, lack of surgical lengthening procedures, greater proportion of intact residual colon, intact ileocecal valve, and care at a non-transplant intestinal rehabilitation center (8, 11, 14, 17, 18). Many of these factors have significant co-variance or numerous confounders, making it difficult to identify independent predictors.

Medical enhancement of bowel absorption without surgery using a long-acting glucagon-like peptide-2 (GLP-2) hormonal analog (teduglutide) has been successful in reducing PN requirements in an adult randomized prospective trial (19). Pediatric randomized controlled trials of teduglutide are ongoing. Autologous Intestinal Reconstructive Surgery Autologous intestinal reconstructive surgeries (AIRS), primarily the longitudinal intestinal lengthening and tailoring procedure (LILT, also known as the Bianchi procedure) and the serial transverse enteroplasty (STEP), are options for managing patients with marked intestinal dilation. These operations are often referred to as intestinal “lengthening” procedures, but should be also understood as tapering procedures. Bowel length is the strongest predictor of enteral autonomy, however, the “length” obtained after LILT or STEP may not be equivalent to that of native bowel. Outcomes demonstrate PN weaning following surgery, and improved motility and absorptive capacity in animal models (20-22). However, data comparing long-term outcomes of severe IF patients with bowel dilation managed with AIRS to those managed without AIRS is not available (2, 23, 24). Data from the international STEP registry, an online voluntary database, demonstrated that 47% of the 78 PN dependent patients with available follow-up data who were least seven days old at the time of STEP achieved enteral autonomy, at a median of 21 months after their STEP procedure. Median pre-STEP and post-STEP bowel length was 60cm and 90cm for those who achieved enteral autonomy, with median pre and post STEP bowel lengths of 36cm and 60cm for those who remained PN dependent (22). Multiple STEP procedures on the same patient are technically feasible, but seem to be associated with decreased benefit (25). Delayed complications of AIRS can include re-dilation, intestinal strictures, staple line bleeding, and fistula formation (26-28).

Intestinal and Multivisceral Transplant As of 2014, there were an estimated 1,056 people living in the US with transplanted small intestine, including 606 who received their transplant as children (29). For those with concomitant liver disease the liver is also transplanted, and this may also be done as a multivisceral transplant inclusive of other organs (stomach, duodenum, pancreas, spleen, and/or colon). Survival after intestinal transplant has improved over the past decade, attributable largely to improvements in survival in the first year after transplant (30). For the cohort of pediatric patients transplanted 2007-2009, one and five year survivals were 90% and 75% for those receiving isolated intestinal transplant, and 72% and 60% for those who received intestine and liver. For the whole cohort, survival of the intestinal graft was 65.1% at 1 year and 42.5% at 5 years (29). The most common cause of death and graft loss among these patients is sepsis (30). Complications include viral, bacterial, and fungal infections, acute and chronic rejection of the transplanted bowel, post-transplant lymphoproferative disorder (PTLD), and direct side effects of medications including renal toxicity. For patients who received a transplant between 2002 and 2012, 9.1% of intestine recipients and 6.9% of intestine-liver recipients developed post-transplant lymphoproliferative disorder within 5 years (29). In addition, even in the context of graft survival, not all grafts had sufficient function as of last follow-up to support full enteral autonomy; among transplant recipients with at least 6 months follow-up in the global Intestine Transplant Registry, 25% remained on at least partial parenteral support as of last follow-up (31). The number of pediatric intestinal transplants performed in the US has declined since 2008 (29), likely due to improved results from intestinal rehabilitation programs. Life-threatening Complications of Intestinal Failure Intestinal Failure Associated Liver Disease The development of IFALD begins with cholestasis, followed by progressive fibrosis with variable amounts of periportal inflammation and steatosis, then cirrhosis. Ultimately end stage liver disease with

synthetic dysfunction, hypersplenism, and portal hypertension may develop, requiring liver transplantation for survival (32, 33). Pathogenesis is multifactorial and may include prolonged PN dependence, intravenous soybean-based lipid emulsions (which contain phytosterols), prematurity, sepsis, lack of enteral nutrition, and alterations in the intestinal microbiome (34-36). The exact definitions of IFALD vary between studies, but in general the diagnosis requires IF, long-term PN dependence, and cholestasis not attributable to other causes of liver dysfunction (e.g. serum direct bilirubin ≥2 mg/dL over two consecutive weeks, often accompanied by elevated serum liver transaminases) (37). A multicenter cohort studied from 2000-2004 that evaluated infants with >60 day PN dependence found a 74.4% incidence of cholestasis, with a 3 year survival of 73% in the cholestatic group (12). Two European studies in the child age group from the 1990s-2000s with PN dependence >3 months and >2 years found IFALD incidence to be 27% and 57% respectively (38, 39). Among patients with IFALD, 74-94% have some degree of fibrosis on biopsy (39, 40) and rates of cirrhosis range from 1327% (32, 37). The best treatment for IFALD is transitioning to full enteral nutrition, which typically leads to resolution of cholestasis and inflammation while liver fibrosis and steatosis can persist on biopsy (4042). Effective hepatoprotective strategies of PN management over the past 15 years have significantly decreased the proportion of children who progress to end stage liver disease. Since long-term PN series from the early 2000s highlighted the hepatotoxicity associated with IV soybean-based lipid delivery, lipid restriction has been used in efforts to treat and prevent IFALD (43, 44). In one prospective study, IV soybean lipid restriction to 1g/kg/d among neonates with IFALD led to a decline in total bilirubin at a rate of 0.63 mg/dL/week (45). In 2006, the use of intravenous fish oil at 1g/kg/d for the treatment of IFALD in infants was reported (46). This therapy results in resolution of cholestasis in 50-75% of patients, decreased mortality, and reduced need for transplantation (47, 48). In a report of children treated between 2002 and 2014 who had liver biopsies, the 23 patients who had cirrhosis on biopsy had similar

one and five year transplant-free survival rates compared to the 126 patients who did not have cirrhosis on biopsy. Cirrhosis was not associated with a decreased likelihood of achieving enteral autonomy. This suggests that in the setting of clinical stability, histopathological diagnosis of cirrhosis does not necessarily portend progression to end stage liver disease necessitating transplant (7). Another promising strategy for the prevention and treatment of IFALD include the use of SMOF lipid (soybean oil, median chain triglycerides, olive oil, fish oil) (49). Future randomized controlled trials comparing these various lipid management strategies are necessary to determine the best long-term strategy; these will need to assess not only liver disease, but also long-term growth and neurodevelopmental outcomes (5052). Additional extended studies of IF patients with clinically stable cirrhosis are also needed (7). Optimal surveillance for patients with significant liver damage remains to be defined but may include regular liver ultrasounds, laboratory monitoring with alpha-fetoprotein, and endoscopic screening for varices. Central Line Associated Bloodstream Infections The incidence of CLABSI among children on long-term PN ranges from 1.3 to 10.2 per 1000 catheter days (12, 38, 53-55), with higher risk in children with SBS, age <1 year, and Medicaid insurance (38, 56). Strategies to reduce the risk of CLABSI comprise of avoiding femoral access sites, using single lumen catheters, and ethanol lock therapy (54, 55, 57, 58). Meticulous line care at home is essential and requires hand washing, sterile dressing changes, cleansing the hub with ethanol prior to accessing, changing intravenous tubing regularly, and avoidance of swimming (59). In one pediatric home PN series CLABSIs accounted for 11% of the mortality, while admissions for CLABSIs and fever without CLABSI accounted for up to 35% of all admissions (60). Not only are central line infections potentially deadly, they are also associated with motor developmental impairments, increased rates of venous thrombosis, need for repeated procedures and anesthetic exposures, high antibiotic usage, and they play a role in the pathogenesis of IFALD (61, 62). Frequent admissions for suspected CLABSI contribute to high healthcare resource utilization and can negatively impact quality of life (63).

Catheter Related Central Venous Thrombosis Catheter related thrombosis may be related to a fibrin sheath around the catheter tip, an intraluminal catheter thrombus, or venous thrombosis (64). The incidence of catheter related venous thrombosis in pediatric IF has been reported as 0.2 to 1.7 per 1000 catheter days or a prevalence of 2057% (38, 52, 65, 66). Risk factors that have been identified are: catheter malposition, repeated catheterizations, SBS, and CLABSI (64). Across different pediatric IF series, on average each patient required 2.2 to 4 central venous catheters over a range of 2.2-2.75 years (5, 67), with the most common reasons for catheter replacements being infection, mechanical problems, and thrombosis. Studies examining the long-term outcomes of children with IF who develop catheter related venous thrombosis are limited with regards to post thrombotic syndrome and pulmonary emboli. A potential complication of recurrent catheter related thrombosis is loss of central venous access, which is an indication for small bowel transplantation as PN can no longer be reliably provided (68). In one series of pediatric IF patients referred for intestinal transplantation, 10.3% were referred due to difficulty in securing central venous access (69, 70). Chemical thromboprophylaxis with low molecular weight heparin or vitamin K antagonists have shown promise in protecting against venous thrombosis, but larger studies are needed to assess efficacy and balance benefits with risk of anticoagulation (67, 71). Attempts to reduce the number of repeated catheter placements required include attempts at line salvage for CLABSI, catheter repair for breakages, and avoiding ligation of vessels at catheter placement (72, 73). Should conventional venous access become limited, interventional radiologic techniques encompassing the use of alternate routes for central access (e.g. azygous, transhepatic, vertebral, and collateral venous catheters), and venous recanalization are being increasingly and successfully utilized (70, 74).

Other Complications Small Bowel Bacterial Overgrowth Small bowel bacterial overgrowth (SBBO) is a frequent complication among children with SBS that evolves over time. Symptoms are bloating, abdominal pain, poor growth, nausea, diarrhea, and/or steatorrhea. SBBO can also cause malabsorption with micronutrient deficiencies due to inflammation or deconjugation of bile acids and is associated with prolonged PN dependence (75, 76). In severe cases Dlactic acidosis can develop due to production of D-lactate by bacteria, which presents with metabolic acidosis and neurologic symptoms such as delirium, ataxia, and slurred speech (77). Evidence based management algorithms to guide chronic therapy are lacking, and the side effects of long-term exposure to antibiotics and the imprecise manipulation of an already abnormal intestinal microbiome remains unknown. Surgical management to address severely dilated intestinal segments in IF can be useful (78). Micronutrient Deficiencies Since children with IF lack sufficient gastrointestinal absorptive function necessary to support normal growth and/or maintain normal fluid and electrolyte homeostasis, it follows that they are at risk for micronutrient deficiencies. Loss of specific regions of the intestine predispose to certain micronutrient deficiencies (Table 2). Mucosal inflammation, small bowel bacterial overgrowth, and occult blood loss may also be contributory. Patients typically receive adequate vitamins while receiving full PN support, but deficiencies often emerge with transitioning to enteral nutrition (79). Total body sodium depletion due to high GI losses can be an issue both on and off PN; this manifests as poor growth and can be evaluated by urine sodium (80). Children with cholestatic liver disease are at risk for Vitamin K deficiency even with supplementation (81); they may also develop copper deficiency if copper supplementation is reduced or eliminated in the setting of cholestasis due to the biliary excretion of copper (82, 83). It was not until the past decade that guidelines were updated to include routine addition of iodine to PN, and even current levels may be insufficient, risking thyroid dysfunction (84).

Shortages of IV multivitamin or trace element infusions have also led to deficiencies in PN dependent children (85). In a retrospective review of patients transitioning off PN (86), serum Vitamin 25-OH D, A, E, B12, folate, copper, iron, zinc, magnesium, phosphorous, and selenium levels were examined. During the phase of transition from PN to enteral support, 33.1% of patients had multiple micronutrient deficiencies: 56% were deficient in at least one mineral and 35.4% in at least one vitamin. Among patients on full enteral nutrition, 27.5% had multiple micronutrient deficiencies, with 25% deficient in at least one mineral and 42.5% in at least one vitamin. The most common deficiencies were iron, copper, and fat soluble vitamins. Predictors of micronutrient deficiency after weaning from PN included longer PN duration and weight or height for age Z-scores <-2. After successful transition to full enteral nutrition, close monitoring with micronutrient supplementation as necessary can protect against vitamin deficiencies. Metabolic Bone Disease Children with IF are at risk for metabolic bone disease due to inadequate intake or absorption of calcium, phosphorous, and vitamin D, leading to impaired bone mineralization and secondary hyperparathyroidism, which stimulates bone resorption. Other negative influences on bone health include concomitant renal osteodystrophy and decreased physical activity among medically fragile patients (61). When measured by screening whole body Dual-energy X-ray absorptiometry (DXA) scan, 34-43% of children with IF have a bone mineral density (BMD) z-score less than -2 (87, 88), and 50-70% have scores less than -1 (87, 89). These children have a high prevalence of vitamin D deficiency (2763.8%), and high rates of hyperparathyroidism (25-44%). Screening for low BMD in pediatric IF patients begins at age 5 as this is when reference normative data are available. DXA scan with bone age determination are then done every two years. Strategies to promoting normal bone mass attainment

include optimization of calcium and vitamin D status, weight bearing exercise, and endocrinologic evaluation for refractory low BMD or complications such as bone pain and fractures. Renal Complications Children with IF are at a higher risk for long-term impaired renal function as many are born prematurely and have complicated neonatal hospitalizations with hemodynamic instability, sepsis, decreased visceral perfusion, and/or exposure to nephrotoxic agents, all of which predispose to renal disease. Further episodes of dehydration related to malabsorption may result in progressive damage. Long-term PN dependence itself is also associated with a decrease in glomerular filtration rate (90). In one study of pediatric IF patients receiving yearly abdominal ultrasounds, 43% had increased renal echogenicity or nephrocalcinosis (91). These ultrasound findings were not reflective of elevations in serum creatinine or urea, but they were associated with higher urine calcium to creatinine ratios, urine oxalate, and serum phosphate. While the natural history of these findings is not yet known, close surveillance is warranted as renal injury in early life may predispose to hypertension and kidney disease in adulthood. Minimization of nephrotoxic agent exposure, prevention of sepsis, and regular monitoring of blood pressure are central tenets of management. Oral Aversion Among patients who develop IF as neonates, oral aversion is common. Critical oral-motor skills for feeding develop during the first three years of life, especially during the first six months (92). Without oral feeding during this key time period, children may develop food refusal or have delayed oral-motor skills (93). Feeding via gastrostomy tubes is utilized in many patients to deliver adequate nutrition and facilitate weaning of PN, which can potentiate oral aversion by reducing appetite and causing caregivers to decrease oral provisions (94). Although data to determine best practices for the prevention and treatment of oral aversion is lacking, multidisciplinary bowel rehabilitation centers often utilize feeding therapists. Oral stimulation is introduced as early in life as safely possible through

nonnutritive sucking or oral feeding. In addition, feeding therapists help caregivers with strategies that will establish positive associations with oral feeding: exposure to the social aspects of eating and avoidance of negative coercive attempts at oral feeding are typical strategies (94, 95). Gastroesophageal reflux and vomiting should be treated. Data on the effect of feeding schedule on oral intake is inconclusive. While bolus feeding may better mimic normal mealtime patterns, continuous overnight feedings may suppress hunger less during the day time and under some circumstances may improve intestinal absorption (96, 97). Chronic Gastrointestinal Inflammation Another potential barrier in enteral nutrition advancement is GI inflammation, which may present as diarrhea, hematochezia, iron-deficiency anemia from occult GI blood loss, and/or emesis. Common causes of GI inflammation among children with IF include SBBO, peptic disease, or allergy (75, 98, 99). A review of children with IF who underwent endoscopic evaluation found that 15% had peptic disease, which in most cases prompted acid suppression therapy with a proton pump inhibitor, and 1547% had allergic or eosinophilic inflammation (75, 98, 99). The colon was the most common site of eosinophilic inflammation and correlated with peripheral eosinophilia and hematochezia. In other disease states such as inflammatory bowel disease, long-term consequences of chronic GI inflammation can be associated with growth impairment and risk for GI malignancy; it is unknown whether any of these risks can be extrapolated to the chronic GI inflammation seen in some children with IF (100). Growth Impaired nutrition absorption or delivery and prematurity are obvious risk factors for poor growth. Available studies are mostly single center series that include patients from over 2 decades ago, when management algorithms and survival rates were different. In some cohorts, improvement in BMI Z-scores may be seen after initiation of PN, though IFALD and CLABSI are associated with lower weight and height Z-scores (52). One long-term study (mean 15.1 year follow-up) of 78 surviving patients who

had neonatal SBS found satisfactory growth in children regardless of whether they remained on PN (101). However, 15.4% of survivors were weaned off PN and subsequently required re-initiation of PN or enteral tube feeds due to poor growth, with significant deviations in height and weight gains within 4 years of PN cessation. Ultimately most patients were able to approach 95% of their genetic target height. Patients who had poor growth after weaning off PN tended to have less residual small bowel length, absent ileocecal valve, and longer initial PN duration. Faltering growth trends may be subtle, and warrant long-term follow-up after PN discontinuation (5). In contradistinction, other studies have found poorer long-term growth outcomes in patients permanently weaned off PN or persistently on home PN. One cross sectional series examined 40 children and adults, mean age 14.8 years, who had SBS as infants and subsequently weaned off PN (102). The children had significantly lower age adjusted weight and height despite normal mid-parental target height, while an even greater proportion of adults had height below the target height range despite normal BMI for most patients. In a study of 45 pediatric IF patients still on prolonged home PN, with median PN duration of 5 years, 50% had height less than -2.0 standard deviations from reference. Patients with intestinal mucosal inflammation or enteropathy were significantly shorter in stature (103). Neurodevelopmental Outcomes Large scale assessments of long-term neurodevelopmental outcomes are lacking. In a study of 15 patients, most of whom were still on PN, 12 had normal (within 2 standard deviations) cognitive outcomes based on psychometric testing, while 11 had normal neurodevelopment and cognitive outcomes based on examination and psychometric testing at a median follow-up of 17 months (104). Not surprisingly, prematurity, longer hospitalizations, and higher number of surgical procedures requiring general anesthesia were associated with impaired cognitive outcomes. In a longitudinal study of 33 patients, more than half had gross motor delay at 12-15 months corrected age (50), while incidence of delays (more than 2 standard deviations below average) in fine motor, language, visual

reception, and learning ranged from 9.4-18.8%. Variables associated with poorer outcomes included prematurity, lower birth weight, central nervous system morbidities, NEC, longer NICU length of stay, higher number of surgeries, and conjugated hyperbilirubinemia. Neurodevelopmental assessments in IF patients who reach school age or adulthood are warranted. Quality of Life Given the complex medical needs of children with IF and growing emphasis on patient and family-centered care, health-related quality of life (HRQoL) is a metric that warrants further study. Various cross sectional surveys of parents and/or pediatric IF patients at intestinal failure centers who were clinically stable on outpatient management found mostly worse HRQoL based on PedsQL questionnaires when compared to healthy controls, though one study did report comparable scores to healthy peers (105-107). Frequent abdominal pain was associated with poorer HRQoL and higher levels of parental stress while higher stool frequency was associated with increased parental stress (105). Interestingly, PN dependence was not associated with greater parental stress or worse HQRoL (105, 107). Practices to optimize patient HRQoL and ameliorate family stressors have not been extensively studied and how health-related quality of life evolves longitudinally remains to be evaluated. Transition to Adulthood The most common causes of pediatric IF are neonatal in onset (7), and as a result children grow up relying on teams of medical professionals and family caregivers for their everyday survival. As more children are now surviving into adulthood, patients and their families often struggle with transition to adult care (108). The process of supporting a teen or young adult's independence in managing complex life sustaining therapies can be daunting. The field of IF may be able to learn from other disciplines in which improved survival of childhood diseases has necessitated the development of models to support that transition, such as cystic fibrosis and congenital heart disease (109, 110). Successful transition to adult care is a gradual process that prepares the patient and family over the course of years, and it also

necessitates the availability of adequate adult programs that can assume care for these patients. The adult years present a host of new psychosocial challenges, and the medical complications of lifelong PN dependence or history of pediatric IF have yet to be fully discovered. In addition the implications for diseases of aging, such as the development of metabolic syndrome or cardiovascular risk, remain unknown. The ability to support conception, pregnancy, and breastfeeding in PN dependent women has been established, but there is little precedent to guide monitoring and nutritional support in young women with a history of severe IF who achieve enteral autonomy and subsequently conceive (111, 112). Conclusion Over the last two decades there have been significant changes in the management of pediatric patients with severe intestinal failure, resulting in unprecedented long-term survival rates for even the most severely affected patients. Multidisciplinary intestinal rehabilitation programs now routinely report survival rates above 90%. Significant barriers in the assessment of long-term outcomes include the lack of uniform definitions between series, inadequate assessments of quality of life related domains, and a paucity of current prospective multi-center cohort studies. Innovative strategies to address the life threatening complications of parenteral nutrition dependence, including progressive intestinal failure associated liver disease, central line associated bloodstream infections, and loss of vascular access continue to be areas of active research. In intestinal and multivisceral transplant, mortality on the wait list has declined, survival post-transplant has increased, and immunosuppression regimens continue to evolve. As a new generation of children are surviving long-term, there must be an increased focus on how best to help them thrive: to prevent morbidity, maintain good quality of life, and to live full and healthy lives throughout adulthood (113).

Figure 1. Nutritional requirements by age

1.6

1.4

Energy

100

Protien 1.2 75 1 50

0.8

25

Average Daily Protein Requirement (g/kg/day)

Average Daily Energy Requirement (kcal/kg/day)

125

0.6 0

2

4

6

8 10 Age (years)

12

14

16

18

Energy requirements birth to 3 years and all protein requirements and from the US Food and Nutrition Board of the Institute of Medicine National Academy of Sciences mean requirements (13). Energy requirements age 4-18 calculated using US Centers for Disease Control 2000 50th percentile weight for age and Estimated Average Requirements (EARs) set by the UK Committee on Medical Aspects of Food and Nutrition Policy (COMA) in 1991, to represent total population norms, not stratified by physical activity level (114, 115). Male and female requirements averaged together.

Table 1. Recent reported survival for children with severe intestinal failure cared for at intestinal rehabilitation programs Reporting site: year published

N

Year of

Inclusion criteria

Survival

cohort

Transplant free survival

Boston, USA: 2016 (7)

313

2002-2014

>90 days PN

94%

89%

Paris, France: 2016 (5)

217

2000-2013

>90 days PN, discharged on home PN

97%

91%

Helsinki, Finland: 2015 (116)

48

1988-2014

>90 days PN or SB length <25% predicted

92%

92%

Toronto, CA: 2015 (117)

33

2006-2009

Children assessed for intestinal transplant

76%

67%

PIFCON Multicenter: 2012 (12)

272

2000-2006

PN >60 days, initiated within 1st year of life

75%

57%

Ann Arbor, USA: 2011 (1)

60

2005-2009

>50% small bowel loss and >60 days PN

93%

93%

Table 2. Summary of commonly encountered micronutrients deficient in pediatric intestinal failure. Micronutrient Signs and symptoms of deficiency

Reasons for deficiency in children with intestinal failure

Vitamin A

Night blindness, xerophlathmia, Bitot's

Fat malabsorption.

spots Vitamin D

Rickets, osteomalacia, hypocalcemia,

Fat malabsorption. Inadequate dietary intake

hypophophatemia, cranial bossing,

or sun exposure. Renal disease.

costochondral beading Vitamin E

Hemolytic anemia, increased red blood

Fat malabsorption.

cell fragility. Wide-based gait, decreased deep tendon reflexes Vitamin K

Coagulopathy

Fat malabsorption. Liver disease. Antibiotics.

Vitamin B12

Megaloblastic anemia. Ataxia, wide-

Ileal resection, intrinsic factor deficiency,

based gait, decreased deep tendon

achlorhydria. Small bowel bacterial

reflexes.

overgrowth. Inadequate dietary intake.

Megaloblastic anemia. Stomatitis,

Lack of jejunal absorption. Liver disease.

Folate

glossitis. Neural tube defects in pregnancy. Sodium

Growth failure

High stool losses

Iron

Microcytic anemia, fatigue, pallor

Chronic or acute blood loss. Absence of duodenum and proximal jejunum. Breast milk without supplementation.

Copper

Microcytic anemia, neutropenia, low

High GI or bilious losses. Zinc toxicity.

bone mineral density

Elimination from PN in the setting of cholestatic liver disease.

Selenium

Cardiomyopathy, myositis

Un-supplemented PN. Cystic Fibrosis.

Zinc

Acrodermatitis eneteropathica, poor

Ileal resection. High GI losses.

wound healing, alopecia. Growth failure. Decreased taste acuity.

GI: gastrointestinal. Fat malabsorbtion may be multifactorial, due to ileal resection, cholestatic liver disease, and/or pancreatic insufficiency, which can lead to fat soluble vitamin deficiencies. Adapted from (118-120)

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