New and Emerging Therapies for Short Bowel Syndrome in Children

Short bowel syndrome is defined as malabsorption following massive resection of the small intestine. In pediatrics, most short bowel syndrome begins in infancy following resection either for necrotizing enterocolitis or in children with gastrointestinal anomalies such as intestinal atresia, gastroschisis or omphalocele. Reduced absorptive surface area results in varying degrees of mal-absorption, but other factors also play a role, including loss of the ability to secrete gastrointestinal regulatory peptides and trophic hormones and loss of gastrointestinal immune function (¹).

NUTRITIONAL THERAPY

The clinical management of short bowel syndrome is a multi-stage process beginning with parenteral nutrition, transitioning through varying stages of enteral nutrition and pharmacotherapy, and hopefully, ending up with a patient who can eat in a relatively normal fashion without supplemental intravenous or continuous enteral nutrition (²). The primary challenge during the first stage of therapy is maintaining fluid balance which is often best accomplished through continuous replacement of ongoing ostomy losses with the solution relatively high in sodium content, usually 80 to 100 mEq/L, to maintain fluid and electrolyte homeostasis. Once fluid and electrolyte losses have diminished, enteral feeding is initiated. Chemically defined peptide or amino acid-based diets are usually used at this stage to facilitate absorption. In small infants, these formulas are also important because they reduce the risk of secondary allergic inflammation in the gut, a situation that may arise when the mucosal barrier is disrupted. These formulas are initiated at a very slow rate and often at a dilute concentration. The concentration is increased followed by a gradual advancement in rate concurrent with an isocaloric reduction in parenteral nutrition.

Continuous enteral infusion has many advantages over bolus feeding, especially in small infants. Enhanced absorption is facilitated by saturation of transporters in the gut 24 hours per day. Providing aggressive enteral nutrition reduces the need for parenteral nutrition as early as possible and significantly reduces the hepatic injury caused by parenteral nutrition, the primary cause of morbidity and mortality in infants with short bowel syndrome. Portable infusion devices make continuous enteral infusion quite possible even in small children. However, enteral nutrition bypasses the cephalic and oral phases of digestion as well as intestinal adaptation, so some oral feedings should be initiated very early, even if only in small quantities. This will allow the child to learn how to suck and swallow. Failure to do this will often result in feeding aversion and abnormal feeding behaviors later in life.

Children over 2 years of age can often be managed quite well with a more complex diet at a reduced cost. Allergic injury to the gut after this age is less common, and more complex protein formulas have the advantage of inducing improved gut adaptation. Enteral feeding formulas should also be relatively high in fat and low in carbohydrate in infants and small children if possible, as these create a lower osmotic load on the gut and provide less substrate for bacterial overgrowth in the small intestine.

Continuous enteral infusion may be gradually advanced based on several parameters. Stool losses increasing more than 50 percent over baseline usually contra-indicate further advancement of enteral feedings. Likewise, losses greater than 40 to 50 ml/kg/day, or stool or ostomy output strongly positive for reducing substances, suggest that enteral feedings should not be further advanced. Solid food introduction should occur at developmentally appropriate times, although earlier introduction of high fat foods, such as meats, is often of significant benefit. This reduces the risk of osmotic diarrhea associated with high carbohydrate feedings.

One of the primary reasons for aggressive use of enteral feeding is the stimulation of gut adaptation. Significant mucosal hyperplasia occurs following massive resection, but this process is heavily based on the provision of aggressive enteral feeding. Fats, particularly long-chain fats, appear to be particularly beneficial in inducing adaptation, although all nutrients may play a role. The choice of diets should take into consideration the age of the child, the functional anatomy of the remaining small intestine and the primary need for maximum caloric absorption. In most instances, diets relatively high in fat, low in simple carbohydrates, and if an intact colon is present, relatively high in complex, slowly-absorbed carbohydrates are often beneficial. One must keep in mind that small-bowel bacterial overgrowth is a major complication in patients with short bowel syndrome and use of diets high in carbohydrate create an ideal substrate for bacterial proliferation.

DRUG THERAPY

Pharmacologic therapy, in addition to dietary therapy, may be important in patients with short bowel syndrome. While the initial reports of growth hormone and glutamine stimulated great interest in use of pharmacologic agents to augment mucosal hyperplasia, further studies in this area have not been confirmatory. Proof of efficacy has been severely limited by lack of double-blind, placebo-controlled trials and the variation in anatomy and other associated clinical problems in many of the subjects. Animal studies have been somewhat more beneficial and have suggested that certain other hormonal factors, such as epidermal growth factor and glucagon-like peptide 2, may be more beneficial. Further studies are needed to ultimately determine the role of these agents in the treatment of short bowel syndrome. Other pharmacologic agents, such as those to slow gut motility (i.e., Loperamide, and Octreotide, a long acting somato-statin analogue which has anti-secretory properties) are occasionally employed.

COMPLICATIONS

Short bowel syndrome is fraught with many complications. During the parenteral nutrition phase, septic complications associated with parenteral nutrition and parenteral nutrition-induced liver disease are major problems. Minimizing catheter sepsis, aggressive use of enteral feedings and careful attention to appropriate use of parenteral nutrition may help to reduce the risk of TPN-induced liver disease. The role of ursodeoxycholic acid is controversial and, although it may have an ameliorating effect on liver injury based on assessment of bilirubin and serum enzyme levels, it is not clear that the agent is effective in improving long-term outcome. Delayed gastric emptying and gastroesophageal reflux are common, so acid secretory inhibitors are frequently indicated.

Once patients are weaned from parenteral nutrition, nutritional deficiency states become somewhat common. Patients should be routinely assessed for calcium, magnesium, and zinc deficiencies, as well as fat-soluble vitamin deficiency (A, D, E, and K).

Small bowel bacterial overgrowth is another complication that may result in significant morbidity in short bowel syndrome. Because the small bowel is often dilated and motility slowed for compensatory reasons, removal of bacteria from the small bowel is impaired and overgrowth of certain invasive organisms may result in invasion and damage to the mucosal surface. In addition, it appears that absorbed bacterial antigens may themselves institute a further inflammatory reaction that may significantly impair both adaptation and transport of nutrients. Rotating or continuous antibiotic therapy is often indicated and, while the selection of the appropriate antibiotic may be directed by culture, it is often impossible to assess which of the various organisms growing in the gut is responsible for the mucosal injury. For that reason, trial and error may be the best means of selecting antibiotic therapy. Several different therapeutic protocols have been used including metronidazole with trimethoprim sulfamethoxazole, amino glycosides such as gentamicin, extended spectrum penicillins and cephalosporins as well as tetracycline.

SURGICAL THERAPY

In some instances, further surgical therapy may be indicated. Surgical strategies for slowing intestinal transit are generally not helpful in children because of the enhanced risk of the development of small bowel bacterial overgrowth. Operations to reduce dilatation, improve motility, and extend surface area, such as the Bianchi procedure, may be helpful in cases of dilated bowel and slow motility.

Utilization of all of these techniques will often permit patients with short bowel syndrome with surprisingly short segments of gut to eventually be weaned free of parenteral nutrition. However, in some instances, usually due to progressive liver disease, intestinal transplantation is indicated. Occasionally, in a small subgroup of patients who have not had an aggressive attempt to induce adaptation and in whom adequate small bowel length exists, liver transplantation alone may be indicated if severe parenteral nutrition-induced liver disease exists. However, this is a small minority of patients. Often, a combined liver/small bowel transplant is needed or, in the case of extreme short bowel syndrome, transplantation may be performed using an isolated intestinal graft early in the course of liver disease. In the absence of any untoward effects of parenteral nutrition, transplantation should usually be avoided, as long-term survival varies from 50 to 70 percent with a transplant and is often greater than 90 percent with the use of long-term parenteral nutrition.

CONCLUSION

Short bowel syndrome is a chronic condition requiring a great deal of patience and attention to multi-stage therapy, careful screening for complications and constant re-evaluation. Therapeutic decisions should be measured in months to years rather than in days to weeks. Ultimately, patients with surprisingly short segments of small bowel may be successfully weaned from parenteral nutrition, although the entire process may take several years. Intestinal transplantation should only be considered as a last resort.