Treating paediatric short bowel syndrome

Short bowel syndrome (SBS) is a rare and potentially life-threatening condition characterised by a reduction in intestinal length, usually as a result of extensive surgical resection. This affects the ability to absorb nutrients, electrolytes and fluid.

Common causes of SBS in children include necrotising enterocolitis (NEC), gastroschisis, intestinal atresia and midgut volvulus.¹ SBS is the leading cause of intestinal failure (IF) in children. IF occurs when the gastrointestinal tract is unable to absorb sufficient nutrients, water and electrolytes to maintain adequate growth. NEC is the most common cause of SBS and its incidence is expected to rise due to the increased survival rates of premature neonates.²

Malabsorption

In addition to the reduced intestinal surface area for absorption, other mechanisms may contribute to the malabsorption in SBS. Gastric acid hypersecretion inactivates pancreatic enzymes and this can impair the absorption of nutrients.² Increased gastric acid secretion may also cause diarrhoea¹ and increase stoma output. Due to the loss of intestinal mass, there is also a reduction in digestive enzymes responsible for carbohydrate digestion and absorption.²

Intestinal adaptation

Following resection, the intestine undergoes a process of adaptation whereby it increases in mass and surface area and this ultimately improves its absorption function.³ Several factors are associated with successful adaptation including length of remaining bowel, presence of ileocecal valve, functional integrity and type of small bowel remaining (the ileum adapts better than the jejunum) and presence of intact colon.^2–5 The age at which resection occurs is an important factor affecting adaptation because preterm neonates have a greater potential for bowel growth.⁶ Due to the differences in intestinal growth, it may be preferable to describe the remaining bowel length as a percentage of the expected length based on the age or size of the child.³ SBS can be defined as a reduction in intestinal length of more than 50%.

Management of SBS

The main aims in the management of SBS are to maintain growth and development, promote intestinal adaptation and prevent complications.^2,3 This requires a multidisciplinary team, referred to as the nutrition support team (NST), which consists of a paediatric gastroenterologist, dietitian, nurse and pharmacist. Input of a NST has shown to have beneficial effects on patient outcomes, as well as potentially reducing healthcare costs.⁷

• Enteral nutrition

Optimal nutritional support is important for growth and development. The gastrointestinal tract is the most physiological and safest way of feeding and nutrition may be given orally or via an enteral feeding tube. Enteral nutrition has an essential role in promoting intestinal adaptation by stimulating the release of hormones from the gastrointestinal tract,^2,3,6 and so it should be started as soon as possible after surgery. Oral feeding has the advantage of maintaining sucking and swallowing functions. However, many infants with SBS develop oral aversion as a result of the numerous interventions during their prolonged hospital stay. Continuous enteral tube feeding is beneficial as it increases contact time with the intestinal mucosa and so absorption may be maximised. Enteral feed tolerance is measured by evaluating stool output and vomiting.

• Parenteral nutrition

Parenteral nutrition (PN) is the mainstay of treatment in SBS. It enables the provision of adequate fluid, electrolytes, macro- and micronutrients to maintain hydration and electrolyte balance and promote growth and development during the period of intestinal adaptation. As enteral feeds are increased, PN is weaned with careful management from the NST. PN may be required for several years until full enteral autonomy can be achieved, so parents/carers are trained to administer PN at home. Guidelines from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition and the European Society for Clinical Nutrition and Metabolism, published in 2005, detail the current standards for paediatric PN.⁸ An update to these guidelines is expected to be published soon.

The most important complications of SBS are related to PN. Patients require long-term central venous access for PN administration. Infection is the most common complication associated with central venous catheters (CVCs) and can cause significant morbidity and mortality. Adherence to aseptic procedures when handling CVCs is essential to prevent catheter-related bloodstream infections (CRBSIs). Taurolidine, a derivative of the amino acid taurine, has antimicrobial and antifungal activity and is associated with a decreased incidence of CRBSIs when administered as a line lock to patients at risk of infection.⁹

IF-associated liver disease (IFALD) is a frequent and severe complication affecting children with SBS who are on long-term PN. Clinically, it can be defined by hyperbilirubinaemia (>50µmol/l) and serum alkaline phosphatase and gamma-glutamyl transferase >1.5-times the upper limit of normal. Hepatic steatosis, cholestasis and hepatic fibrosis can occur, with possible progression to cirrhosis and liver failure.² Onset of IFALD may be specifically related to the PN composition and administration. Lipids provide a source of non-protein calories and essential fatty acids for patients receiving PN, and also enable fat-soluble vitamins to be included in the PN formulation.

However, use of soybean oil-based intravenous lipid emulsions (ILEs) may contribute to IFALD. They contain a higher proportion of omega-6 fatty acids, leading to the production of pro-inflammatory substances with the potential to cause liver damage. Soybean oil-based ILEs provide long-chain triglycerides which are less easily hydrolysed by lipoprotein lipases than medium-chain triglycerides.¹⁰ Fish oil-based ILEs provide a source of anti-inflammatory omega-3 fatty acids, and there is some evidence that the use of a multicomponent fish oil-containing ILE may contribute to a reduction in total bilirubin levels in children with IF on long-term PN.¹¹ Provision of excess glucose and lipid in PN may cause hepatic steatosis, so the PN formulation should be adapted to the needs of the individual patient. Generally, glucose intake should not exceed 18g/kg/day in infants, and lipids should provide between 25% and 40% of non-protein calories.⁸

It is common practice to give ‘fat-free days’ by omitting lipid from the PN formulation for a number of days each week for patients on long-term PN. Cyclical infusion of PN may also reduce the risk of liver complications and so the infusion time is usually gradually reduced from 24 hours to 12 hours, as tolerated. This requires close monitoring of blood glucose, as well as a stepwise increase and decrease of PN infusion rates to prevent hyper and hypoglycaemia. Infants need to be on sufficient enteral feeds to enable them to maintain normal blood glucose control during the time off from PN. The reduction in infusion time enables PN to be administered overnight and encourages oral feeding during the day. It also enables the child to go to school and participate in other activities.

Other risk factors for IFALD include prematurity, recurrent sepsis and lack of enteral feeding. The immature liver of preterm neonates is more susceptible to damage from hepatotoxic substances. Extrahepatic infections (including CRBSIs) cause a release of pro-inflammatory substances that contribute to liver disease.^4,6 Absence of enteral nutrition leads to a lack of stimulation of the enterohepatic circulation and the accumulation of toxic bile salts, causing cholestasis.⁴

• Medicines

Medication may be required to optimise treatment in SBS. Proton pump inhibitors and histamine H2 antagonists can reduce gastric acid hypersecretion. Loperamide can help to reduce stool output by increasing intestinal transit time, and thereby increasing absorption. Children with cholestasis may benefit from ursodeoxycholic acid to improve bile flow.

Surgical management

In children with SBS, the small bowel may become dilated and lose its normal peristaltic activity.³ Surgery may be indicated to increase the functional surface area of the intestine to enhance absorption. Longitudinal intestinal lengthening and tapering (LILT), often referred to as the ‘Bianchi procedure’, involves dividing the dilated bowel in half longitudinally and then joining the two smaller lumens end-to-end to increase intestinal length and halve the diameter.

Serial transverse enteroplasty (STEP) is a procedure where an endoscopic surgical stapler is applied to alternate sides along the length of the dilated intestinal segment to create a ‘zig-zag’ – a longer and narrower channel. Recurrent dilation of the bowel can occur after both procedures. However, unlike STEP, the LILT procedure can only be performed once. Although, these surgical procedures may not lead to enteral autonomy, they may have a role in certain individuals with dilated small bowel and limited enteral feed tolerance.

• Transplantation

Intestinal transplantation is indicated in children with irreversible IF who have recurrent life-threatening CRBSIs, IFALD or loss of vascular access. Patients with mild liver disease are offered isolated intestinal transplantation. However, combined liver and small bowel transplantation is recommended in those with severe IFALD. Isolated liver transplantation is indicated in children with SBS who are unable to achieve intestinal adaptation and enteral autonomy due to end-stage liver disease, provided they have previously tolerated at least 50% of their estimated daily calorie requirements enterally with adequate weight gain.^4,10

The criteria of some transplant centres includes a requirement of at least 30cm of functional small bowel, with or without the ileocecal valve, for this type of transplant.⁴ Data from the two UK paediatric intestinal transplant centres report one-year survival of 85% and five-year survival of 60%.¹² Worldwide survival rates have been reported as 76%, 56% and 43% at one, five and 10 years, respectively, which includes both adult and paediatric patients.¹³

Emerging treatment

The naturally occurring human glucagon-like peptide-2 (GLP-2) is secreted by L-cells of the intestine. Teduglutide is an analogue of GLP-2 and a designated orphan drug. In non-clinical studies, it has been shown to increase villous height and crypt depth,¹⁴ thereby increasing the intestinal absorptive surface area. Carter et al¹⁵ conducted a 12-week open-label study that included 42 patients aged 1–17 years with SBS and who were PN-dependent for at least one year.

Participants either received teduglutide 0.0125mg/kg/day (n=8), 0.025mg/kg/day (n=14), 0.05mg/kg/day (n=15), or standard of care (n=5). Patients in the teduglutide group required PN on seven days of the week at baseline.

Four patients were weaned off PN by week 12 in the teduglutide group (0.05mg/kg, n=3; 0.025mg/kg, n=1), and two of these patients restarted PN after a four-week wash-out period. The greatest reduction in mean prescribed PN volume was seen in the 0.05mg/kg and 0.025mg/kg teduglutide groups. Improvement in enteral nutrition was seen in all four groups, and was maintained after teduglutide was discontinued.

Teduglutide has recently been approved for use in the EU for children with SBS aged one year and above, administered as a subcutaneous injection at a dose of 0.05mg/kg once daily. The cost of 28 vials (5mg strength) is approximately £15,000.

A double-blind, controlled trial is currently being conducted in children with SBS who are PN-dependent.¹⁶ They are randomised to subcutaneous teduglutide 0.05 or 0.025mg/kg/day, or standard of care for 24 weeks. The primary outcome measures are safety and tolerability of teduglutide treatment, and at least 20% reduction in PN volume from baseline. The estimated completion date of this study is June 2017.

Conclusions

In the future, tissue engineering may provide further treatment options in children with SBS. However, current management of these patients can be optimised with a multidisciplinary approach to promote intestinal adaptation, maintain growth and development and prevent potentially life-threatening complications. The ultimate goal is to achieve enteral autonomy and improve the overall quality of lives of these children and their families.

Key points

• Short bowel syndrome (SBS) is the most common cause of intestinal failure (IF) in children
• Provision of optimal nutritional support is essential during the period of intestinal adaptation
• Catheter-related blood stream infections and IF-associated liver disease are frequent complications related to parenteral nutrition
• Some children may benefit from bowel lengthening surgical procedures or intestinal transplantation
• Studies investigating the use of peptides in the treatment of SBS are ongoing.

Author

Jaini Shah MPharm PG Dip GPP
Highly Specialist Pharmacist – Paediatric & Neonatal Nutrition, The Royal London Hospital, Barts Health NHS Trust, London, UK

References

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