Description:
Massive loss of intestinal surface area results in short bowel syndrome, characterized by malabsorption of fluids, electrolytes and other nutrients. Common causes of short bowel syndrome include resection related to volvulus, thrombosis of the superior mesenteric artery, Crohn’s disease or trauma. While some adaptation (characterized by elongation and dilation of remnant bowel) of remaining intestinal surface can improve nutrient absorption, patients with less than 60 cm of functional jejunum or ileum typically require permanent total parenteral nutrition. While intestinal transplantation is one alternative, there has been research interest in methods to increase intestinal adaptation as a nonsurgical alternative.

Specifically, intestinal adaptation is thought to be related to exposure of the remaining mucosa to luminal nutrients, the presence of enteric hormone and pancreatic-biliary secretion and the trophic effects of various extrinsic growth factors and hormone. For example, the amino acid glutamine, administered either enterally or parenterally, is known to induce a trophic or regenerative effect on the bowel. Growth hormone is also thought to have a trophic effect on the bowel.

Specialized inpatient programs have been developed to offer intensive counseling and tailored regimens of diet modification, glutamine and growth hormone therapy to patients with short bowel syndrome. The goal of these programs is to either eliminate or reduce the need for total parenteral nutrition.

Policy:
An inpatient program of intestinal rehabilitation, consisting of metabolic evaluation, patient counseling and education, nutritional counseling, physical therapy and treatment with growth hormone and glutamine is considered INVESTIGATIONAL in patients with short bowel syndrome who are dependent on total parenteral nutrition.

Policy Guidelines
The FDA has noted growth hormone for patients with short bowel syndrome should be limited to patients receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high-carbohydrate, low-fat diet adjusted for individual patient requirements. Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid and micronutrient supplements. Zorbtive is administered daily at 0.1mg/kg subcutaneously up to 8 mg/day. Administration of Zorbtive for longer than four weeks has not been adequately studied per the FDA indications. See also policy No. 50106 for discussion of human growth hormone.

Benefit Application
BlueCard/National Account Issues
Certain individuals on chronic total parenteral nutrition (TPN) considered at high risk for complications may benefit from a period of case management.

State or federal mandates may require coverage eligibility for drugs used according to their FDA-labeled indications, e.g., Zorbtive.

Rationale
The published data are almost exclusively derived from researchers working at the Nutritional Restart Center near Boston. Most reports consist of small case series, many with presumably overlapping patients. One case series consists of 45 patients with short bowl syndrome maintained on long-term parenteral nutrition.¹ These patients were treated with growth hormone, glutamine and a modified diet for 4 weeks and then followed up for an average of 1.8 years. After four weeks of therapy, 58 percent no longer required TPN. At follow-up, the percentage of patients not receiving TPN fell to 40 percent. A review article published in the same year included 67 adults receiving TPN, and presumably includes overlapping patients.² At completion of the 4-week program, the TPN requirement for each patient was noted as either off (52 percent), reduced (38 percent) or no change (10 percent). Over an unspecified follow-up period, there was some attrition of the treatment effect.

The relative contributions of the pharmacologic, dietary and counseling/education aspects of the overall program cannot be determined. Specifically, some researchers have questioned whether the treatment effect was primarily due to meticulous dietary counseling as opposed to any effect from glutamine or growth hormone. For example, Scolapio conducted a randomized six-week, double-blind, placebo-controlled trial of eight patients who alternatively received growth hormone, glutamine supplementation and a high carbohydrate, low-fat diet alternating with the placebo treatment.³ Active treatment was associated with an increased body weight and lean body mass, decreased percent body fat without an increase in fluid or macronutrient absorption. All patients receiving active treatment developed peripheral edema, suggesting that an increase in extracellular fluid may have been responsible for the positive findings. In addition, after discontinuation of growth hormone, the weight returned to baseline. In another blinded crossover study of eight patients, Szkudlarek and colleagues examined the effect of growth hormone and glutamine supplementation on intestinal function.⁴ Unlike the above study, the patients did not receive a high carbohydrate, low-fat diet. Growth hormone with glutamine was not associated with improved intestinal absorption of energy, carbohydrate, sodium, potassium, calcium or magnesium.

An additional research question is the contribution of an intensive inpatient program, compared to similar elements of the program offered in an outpatient setting. This issue has not been addressed in the published literature.

An updated search of the medical literature found that there is no consistent definition or components of intestinal rehabilitation, nor are there long-term health outcomes measured for intestinal rehabilitation. Studies continued to assess the relative contributions of growth hormone, glutamine, glucagon-like peptide-2 and diet but did not assess the optimal treatment settings or components of intestinal rehabilitation according to patient characteristics.

One study involved 12 adults with small bowel who were dependent on a home-based, high-carbohydrate parenteral nutrition diet.^5,6 Patients were randomized in a double-blind placebo-controlled crossover study. Patients received daily low-dose growth hormone and placebo for two- to three-week periods separated by a 1-week washout period. Treatment with growth hormone increased intestinal absorption of energy, nitrogen, carbohydrates and fats. The increased food absorption represented 37 percent +/- 16 percent of total parenteral energy delivery. Body weight, lean mass and D-xylose absorption increased. However, the study did not assess long-term health outcomes beyond the immediate study period.

One study assigned 59 patients with life-threatening complications of intestinal failure to three treatment options.⁷ Sixty-eight percent of patients were considered appropriate candidates for intestinal transplants, 10 percent were managed with rehabilitation, and 17 percent were maintained on optimized parenteral nutrition. All patients managed with rehabilitation were weaned from parenteral nutrition within six months.

Wu and colleagues assessed bowel rehabilitation combined with trophic therapy and found that 33 of 38 patients maintained well body weight and serum albumin concentrations after an average follow-up of 5.9+/-4.3 years for the 33 survival patients.⁸ Nutrient absorption in eight patients treated with growth hormone and glutamine seemed to increase, but the effects occurred only during the treatment period and were not sustained.

The FDA label for Zorbtive indicates growth hormone has been shown in human clinical trials to enhance the transmucosal transport of water, electrolytes and nutrients. The FDA approval for Zorbtive was based on the results of a randomized, controlled, Phase III clinical trial in which patients dependent on intravenous parenteral nutrition who received Zorbtive (either with or without glutamine) over a four-week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support. However, the effects beyond four weeks were not evaluated nor was the treatment location (inpatient vs. outpatient) identified.

References:

1.  Wilmore DW, Byrne TA, Persinger RL. Short bowel syndrome: new therapeutic approaches. Curr Probl Surg 1997; 34(5):389-444.
2. Scolapio JS. Effect of growth hormone, glutamine, and diet on body composition in short bowel syndrome: a randomized, controlled study. JPEN J Parenter Enteral Nutr 1999; 23(6):309-13.
3. Szkudlarek J, Jeppesen PB, Mortensen PB. Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised double blind, crossover, placebo controlled study. Gut 2000; 47(2):199-205.
4. Seguy D, Vahedi K, Kapel N et al. Low-dose growth hormone in adult home parenteral nutrition-dependent short bowel syndrome patients: a positive study. Gastroenterology 2003; 124(2):293-302.
5. Scolapio JS. Tales from the crypt (editorial). Gastroenterology 2003; 124(2):561-4.
6. Fishbein TM, Schiano T, LeLeiko N et al. An integrated approach to intestinal failure: results of a new program with total parenteral nutrition, bowel rehabilitation, and transplantation. J Gastrointest Surg 2002; 6(4):554-62.
7. Byrne TA, Wilmore DW, Iyer K et al. Growth hormone, glutamine, and an optimal diet reduces parenteral nutrition in patients with short bowel syndrome: a prospective, randomized, placebo-controlled, double-blind clinial trial. Ann Surg 2005; 242(5):655-61.
8. Torres C, Sugan D, Vanderhoof J et al. Role of an intestinal rehabilitation program in the treatment of advanced intestinal failure. J Pediatr Gastroenterol Nutr 2007; 45(2):204-12.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

Policy to remain active, but will not undergo scheduled review after 2015.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines

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