Short-Bowel Syndrome Treatment & Management

Indications and contraindications for surgery

Most survivors of massive bowel resections who develop short-bowel syndrome are initially fed by means of total parenteral nutrition (TPN). In these patients, TPN prevents the development of malnutrition and has been shown to benefit patient outcomes. TPN may be administered concurrently with enteral nutrition early in the clinical course of short-bowel syndrome because the ultimate goal in many of these patients is to enhance intestinal adaptation and render patients free of TPN as described by Wilmore et al in animal models. ^[25]

In many patients, intestinal adaptation, alone or in combination with modified and supplemented diets (eg, growth hormone, glutamine, high carbohydrate, low fat) as described by Byrne et al, eventually allows liberation from TPN. ^[23]

Unfortunately, some patients are extremely difficult or impossible to wean from parenteral nutrition. Common characteristics of these patients include very short remaining small-bowel segments (< 60 cm), loss of the colon, loss of the ileocecal valve, or small-bowel strictures with stasis and bacterial overgrowth.

TPN is not a panacea. Access sites become infected or the cannulated vein thromboses, necessitating replacement. Eventually, the patient may run out of usable veins for access to deliver TPN. In addition to these mechanical and infectious complications, many serious metabolic complications are associated with long-term use of TPN. The most clinically important of these are hepatic and biliary derangements. In fact, according to Vanderhoof, advanced liver disease currently is the most common cause of death of patients with short-bowel syndrome. ^[26]

Early in the course of therapy with TPN, nonspecific elevations in hepatic transaminases can be found. Frequently, these biochemical abnormalities are self-limited and require no specific alteration or curtailment of therapy.

The most frequent manifestation of hepatobiliary disease in patients with short-bowel syndrome who are on TPN is cholestasis. ^{[27, 28, 29, 30]} Biliary sludge or gallstones are found in approximately 50% of patients receiving TPN with no oral intake for 3 months.

Progressive hepatic parenchymal damage is the most feared hepatobiliary complication of prolonged TPN. Fatty liver is often observed in adults. Nonalcoholic steatohepatitis has features of fatty change but is associated with inflammatory cell infiltration and fibrosis. Progressive cholestasis and liver injury can lead to outright portal fibrosis or cirrhosis, portending progression to liver failure and a poor outcome. Patients with persistent liver function abnormalities should be identified before progression to cirrhosis to assess candidacy for intestinal transplantation.

Moreno et al reported complication rates and survival data for their cohort of 74 patients maintained on long-term home parenteral nutrition for short-bowel syndrome. ^[20] There were 94 significant complications in the group, most of them infectious. At the end of the year, 74.3% of the patients remained on TPN. The most common cause for termination of support in the other 23.6% was death (52.9%). Others either were switched to enteral nutritional support (11.8%) or could be liberated from specialized nutritional support to return to an oral diet (23.5%).

No firm absolute contraindications to surgery exist in patients with short-bowel syndrome. The only exception to this might be the creation of a small intestinal valve, designed to increase transit time, in a patient who already has stasis or bacterial overgrowth.

Patients who are severely malnourished with very low albumin or prealbumin levels and those with systemic sepsis or with severe coagulopathy because of advanced liver disease should have these conditions corrected before undergoing surgery.

The decision to operate on a patient with short-bowel syndrome requires great judgment. Surgery is undertaken in these patients usually only after all other therapeutic options, such as parenteral and enteral nutrition or pharmacologic bowel compensation, have been exhausted. Others may require operation because of the complications of prolonged parenteral nutrition or stasis of enteric contents and bacterial overgrowth.

Future and controversies

Future developments in the treatment of short-bowel syndrome will consist of finding ways to maximize bowel adaptation and of refining techniques of transplantation and immune modulation.

Pharmacologic bowel compensation has had some good results to date. Better understanding of small bowel trophic signals and the interaction among foodstuffs, enteric hormones, and the intestinal mucosa might lead to improved bowel adaptation.

Transplantation techniques are improving, and factors that negatively impact the success of these operations have been described and discussed. The introduction of tacrolimus was associated with increasing 1-year graft survival rates from 19-57%. Problems still exist. Rates of sepsis and immunosuppression-related malignancies are still high.

The search for the transplantation "holy grail" of donor-specific immunologic tolerance continues. Animal studies by Gorczynski and others suggested that introduction of donor antigens via the portal vein before implantation might help induce a state of tolerance. ^[31] So far, this has not been demonstrated in humans.

The identification of the gamma-delta receptor–positive T (GDT) cell was an exciting discovery. GDT cells are a source of type 2 cytokines, including interleukin (IL)-4, IL-10, and transforming growth factor (TGF) beta. These type 2 cytokines are associated with enhanced graft survival, making the GDT cell an intense research topic.

Patients undergoing massive small-bowel resections frequently experience large fluid shifts and difficulties with volume and electrolyte homeostasis in the early postoperative period. The first priority is to ensure that the patient is adequately resuscitated and hemodynamically stable. Fluid and electrolyte disorders make up the most important group of complications in the early postoperative period in this group of patients, according to Cosnes et al. ^[32]

Scolapio and Fleming described therapeutic guidelines for the fluid and electrolyte management of these patients. ^[33] These include replacement of fluid and electrolytes lost through nasogastric suctioning and in stool. They recommended that 300-500 mL be added to the total volume administered to replace insensible losses. These replacement volumes are added to the patient's calculated daily maintenance volume. Daily urine output should be at least 1 L.

Parenteral nutrition is an important therapy in the care of the patient with short-bowel syndrome. Parenteral nutrition provides adequate protein, calories, other macronutrients, and micronutrients until the bowel has had time to adapt.

The time required for optimal bowel adaptation is a source of controversy. Booth stated that bowel adaptation may not be complete until 1 year or more after resection. ^[34] Carbonnel et al wrote that little bowel compensation occurs after 3 months. ^[35] Data from animal studies conducted by Wilmore et al suggested that supplementing enteral intake with parenteral nutrition early in the postoperative course results in better overall bowel adaptation. ^[5] This is most likely because it facilitates provision of adequate calorie and nitrogen sources.

According to Nightingale et al, when enteral nutrient absorption falls to below one third of premorbid capacity, some amount of parenteral nutrition is needed. ^[36] Parenteral nutrition can be started with standard formulations and administered over the course of 24 hours daily on an inpatient basis. Make efforts to infuse daily requirements in shorter time periods before the patient is discharged. This is called cycling, and it allows liberation from the solution pump for at least some time each day.

In addition, laboratory studies, including serum chemistries and mineral and trace element levels, are monitored frequently and provision of these nutrients adjusted accordingly in the parenteral nutrition formula.

Gradually, most patients are able to resume and increase oral food intake. This is begun by providing small frequent feedings and slowly advancing the diet as tolerated. According to Scolapio and Fleming, the process of weaning the patient off parenteral nutrition can begin once oral calorie intake exceeds 1000 kcal/day. ^[33] Further reductions in parenteral nutrition are predicated on increased oral intake.

Woolf et al reported that nutrient absorption is not complete in patients with loss of half or more of the small bowel. ^[37] Therefore, they usually require 30-40 kcal/kg/day to meet daily energy requirements.

A subset of patients who have lost significant amounts of ileum and colon may have massive fluid losses. Stomal outputs may exceed 2.5 L/day. Many of these patients are likely to be dependent on prolonged intravenous (IV) fluid therapy. Some may do well with oral sources of water, glucose, and sodium. Wilmore's group reported good success with Gatorade. ^[25] Scolapio and Fleming stated that the solution should contain at least 90 mmol/L of sodium. ^[33] This may require supplementation with salt in some of the commercially available solutions.

Despite bowel adaptation and meticulous nutritional therapy, some patients cannot be liberated from parenteral nutrition. These patients usually are those with less than 60 cm of small bowel remaining, loss of the ileum and ileocecal valve, and loss of the colon.

The concept of pharmacologic bowel compensation includes measures aimed at further enhancing bowel adaptation and increasing the chances that even patients with difficult cases can be liberated from parenteral nutrition. ^[38] This approach includes provision of growth hormone 0.03-0.14 mg/kg/day subcutaneously for 4 weeks, parenteral (0.16 g/kg/day) or enteral (30 g/day) glutamine supplementation, and a high-carbohydrate diet with 55-60% of calories coming from carbohydrates versus 20-25% from fat and 20% from protein.

In 1997, Wilmore et al published their results on 87 patients treated with this regimen. ^[25] After 4 weeks, 52% were completely off parenteral nutrition, and an additional 38% had significantly reduced parenteral nutrition requirements. The same investigators published results with this regimen, also in 1997, in 45 patients with a jejunoileal remnant less than 50 cm and with a segment of colon remaining in continuity. After 4 weeks on the regimen, 58% were liberated from parenteral nutrition. After a mean follow-up of 1.8 years, this had fallen to 40%.

Somatropin is a recombinant human growth hormone that elicits anabolic and anticatabolic influence on various cells (eg, myocytes, hepatocytes, adipocytes, lymphocytes, hematopoietic cells). It exerts activity on specific cell receptors, including insulinlike growth factor-1 (IGF-1). Actions on the gut may be direct or mediated via IGF-1. Somatropin is indicated to treat short-bowel syndrome in conjunction with nutritional support. The adult dosage is 0.1 mg/kg/day SC for up to 4 weeks (not to exceed 8 mg/day). Pediatric dosing has not been established.

Teduglutide, an analogue of naturally occurring glucagonlike peptide-2 (GLP-2), was approved by the FDA in December 2012 for adults with short-bowel syndrome who are dependent on parenteral support and gained FDA approval in May 2019 for children as young as 1 year. ^{[39, 40]} It binds to the GLP-2R receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts, and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in local release of intestinal mediators that increase intestinal absorptive capacity, leading to increased fluid and nutrient absorption. ^[41]

In two clinical trials and two extension studies of patients randomly assigned to receive teduglutide or placebo, those treated with teduglutide achieved 46% and 63% clinical responses, compared with 6% and 30% of those treated with placebo. ^[42] A reduction in the volume of parenteral nutrition (after 24 weeks of treatment was also observed. Results showed a mean reduction in parenteral nutrition of 2.5 L/week and 4.4 L/week in teduglutide-treated patients, compared with 0.9 L/week and 2.3 L/week in placebo-treated patients.

Specific drug therapies in short-bowel syndrome are mainly aimed at decreasing gastric hypersecretion or decreasing diarrhea. ^{[43, 44]} Gastric hypersecretion may be treated by proton pump inhibitors (PPIs) or histamine-2 (H2) blockers in the early postoperative period. In most patients, gastric hypersecretion severe enough to cause clinical problems is self-limited.

Diarrhea is a more vexing problem. When the patient is on nothing by mouth (NPO), codeine (60 mg IM q4hr) may be helpful. When enteral intake is resumed, Imodium (4-5 mg q6hr) or Lomotil (2.5-5 mg q6hr) is useful. In refractory cases, tincture of opium (5-10 mL q4hr) may be tried.

Cases involving patients who have lost all of their colon and ileum, with less than 100 cm of jejunum and an end jejunostomy, are the most difficult to manage. In these patients, the somatostatin analogue octreotide can be administered in doses of 100 μg subcutaneously three times a day. This can reduce stool output by as much as 50%. ^[45]

Choice of operative approach

Operative therapies for short-bowel syndrome can be divided into the following two broad categories:

• Intestinal or combined liver-intestinal transplantation
• Nontransplant operations

Nontransplant components of the surgical armamentarium for the treatment of short-bowel syndrome include intestinal lengthening (Bianchi) procedures, intestinal tapering for dilated dysfunctional bowel segments, strictureplasty, and creation of intestinal valves or reversed bowel segments for patients with rapid intestinal transit times.

In 1995, Thompson et al reported results from various nontransplant and transplant surgical procedures in 160 patients with short-bowel syndrome (48 adults and 112 children). ^[46] In this population, the type of operation was selected on the basis of the following criteria:

• Patient age
• Remaining bowel length
• Presence or absence of bowel dilatation
• Overall functional status of the bowel remnant, including intestinal transit time
• Presence or absence of complications related to parenteral nutrition

Fifteen patients had intestinal remnants greater than 120 cm but with dilated dysfunctional bowel, in some cases proximal to a stricture. ^[46] Patients in this group underwent Heineke-Mikulicz strictureplasties (n = 4) or intestinal tapering procedures (n = 11). Intestinal tapering creates a decrease in the circumference of dilated bowel by imbrications or resections of a portion of the antimesenteric side of the intestine. Approximately 87% of these 15 patients experienced clinical improvement.

Small-bowel remnants 90-120 cm associated with rapid intestinal transit times were present in 14 patients. ^[46] Two of these patients underwent creation of an artificial valve, which is made by intussuscepting a distal small-bowel segment and suturing it in place. Both of these patients improved clinically. A reversed segment was placed in one patient but subsequently was taken down because of poor bowel function.

Intestinal lengthening was performed in 14 patients who had short small-bowel remnants that were dilated. ^[46] Intestinal lengthening is performed by transecting the bowel segment along its longitudinal axis between the antimesenteric and mesenteric borders. This converts one dilated loop of intestine into two parallel segments that then are anastomosed in series. Clinical improvement was observed in 86% of these patients.

In 1997, Thompson and Langnas reported additional results from nontransplant operations for treatment of short-bowel syndrome. ^[47] Ninety patients were evaluated for possible surgical therapy.

Of 43 procedures, 37 (86%) yielded clinical improvement. ^[47] The best results were achieved with operations designed to increase intestinal surface area, such as restoration of gastrointestinal (GI) tract continuity and intestinal lengthening (86%), and those intended to correct functional problems, such as strictureplasty, removal of diseased bowel segments, and closure of fistulae (85%). Clinical improvement rates of only 50% were noted with operations aimed at slowing intestinal transit time, such as creation of valves or reversed segments.

In contrast, Panis reported good results with segmental small-bowel reversal. ^[48] However, his series was small (N = 8). The patients had very short small bowel remnants (median, 40 cm). The median length of the reversed segment was 12 cm. One patient died of pulmonary embolism in postoperative month 7. Of the remaining seven patients, three were completely liberated from parenteral nutrition, one required only IV fluid and electrolyte therapy, and three received only three to five nocturnal cycles of parenteral nutrition per week.

Javid et al published their results with serial transverse enteroplasty (STEP) for the treatment of short-bowel syndrome in infants. ^[49] A total of five children underwent this intestinal lengthening procedure. No significant perioperative complications were reported. The percentage of protein-energy nutrition that the patients were able to take enterally increased significantly in this group following STEP (P< 0.05). One child was completely liberated from parenteral nutrition, and another child's severe cholestasis was reversed.

Oliveira et al examined 5-year outcomes after STEP in 12 children (median age, 5.5 months) with short-bowel syndrome. ^[50] Of these 12 patients, two underwent liver-intestinal transplants and two died of liver failure, whereas the other eight all exhibited stable intestinal absorptive capacity at follow-up. Among these eight patients, seven were weaned off parenteral nutrition by age four. Repeat STEP or bowel tapering was not necessary in any of the patients.

Organ transplantation was a later addition to surgical treatment of this syndrome. From the outset, intestinal transplantation faced many hurdles, first and foremost because of the massive amount of lymphoid and immunologic tissue associated with the GI tract. Effective immunosuppressant drugs had to be developed. Techniques and postoperative care had to be refined, and the indications for transplantation had to be clarified. Worldwide, an estimated 25-30 centers are actively engaged in intestinal or liver-intestinal transplantation for short-bowel syndrome.

In 1995, Todo et al reported their experience with 71 isolated intestinal (n = 22), liver-intestinal (n = 30), and multiorgan (n = 11) transplants in 66 patients performed from 1990-1995 at the University of Pittsburgh Medical Center. ^[51] At the time of the report, just over 50% of the patients were alive. Thirty-five grafts had been lost. Sepsis (n = 19) was the most common cause of graft loss, followed by management errors (n = 10) and rejection (n = 6).

The authors performed linear regression analysis to identify factors correlated with graft loss. ^[51] They identified prolonged operative time, inclusion of colon in the graft, a positive cytomegalovirus (CMV) donor infection status, high tacrolimus (FK506) blood levels, use of OKT3, and steroid recycling as predictors of graft loss. During the course of this study, four patients received combined intestinal–bone marrow transplants. They were all doing well at 2-3 months of follow-up.

Langnas et al described their experience at the University of Nebraska with 13 liver-intestinal transplants and three isolated intestinal transplants in infants and children. ^[52] In children who received combined liver-intestinal grafts, the 1-year actuarial patient survival rate was 76%, and the 1-year actuarial graft survival rate was 61%. Six patients had been liberated from parenteral nutrition. All three who received isolated intestinal grafts were alive and free from parenteral nutrition. Most significant complications were related to sepsis and graft rejection.

In 1998, Abu-Elmagd et al updated the University of Pittsburgh experience with liver-intestinal and isolated intestinal transplantation. ^[53] Their results in 59 adults and 39 children were presented. These patients received either liver-intestinal (n = 50), isolated intestinal (n = 37), or multivisceral (n = 17) grafts. Twenty were augmented with donor bone marrow. Tacrolimus was the primary immunosuppressant used in all cases.

With a mean follow-up duration of 32 months, 48% of patients were alive with grafts that allowed complete (91%) or partial (9%) liberation from specialized nutritional support. ^[53] In addition, 12 patients had passed the 5-year milestone. The actuarial patient survival rates at 1 and 5 years were 72% and 48%, respectively. Bone marrow transplantation did not appear to increase graft survival.

In 2007, Sudan et al published their clinical results of intestinal lengthening procedures. ^[54] An outcome analysis of a longitudinal intestinal lengthening (Bianchi procedure) and a serial transverse enteroplasty (STEP procedure) was done. Fifty pediatric patients and 14 adult patients were included in the study. All patients had dilated small bowel loops greater than 3.9 cm in size and also had poor enteral progression. The patients underwent 43 Bianchi procedures and 34 STEP procedures.

The average intestinal length increased from 44 cm to 68 cm for the Bianchi procedure and from 45 cm to 65 cm for the STEP procedure. ^[54] At 1 year after the lengthening procedures, 69% of the patients were off total parenteral nutrition (TPN). The authors of this study concluded that surgical lengthening procedures result in an improvement in enteral nutrition.

Operative details

Patient selection is paramount to operative success. Tailor nontransplant operative approaches to the patient's remaining length of intestine, the presence or absence of strictures or areas of stasis, bowel dilatation, and the intestinal transit time as described above. Various radiographic techniques, including contrast small-bowel follow-through and computed tomography (CT), are helpful in the decision.

Transplant surgery is usually reserved for patients who are dependent on parenteral nutrition, who have run out of venous access, who have had several episodes of central line–related sepsis, or who have begun to manifest progressive parenteral nutrition–associated liver dysfunction. Identify these patients early and perform transplant before hepatic cirrhosis develops. This may obviate the need to perform a combined liver-intestinal transplantation, and results are better in patients who have not yet developed cirrhosis, according to Vanderhoff and Langnas. ^[26]

In the study by Abu-Elmagd et al, grafts were obtained from blood group (ABO) antigen-matched cadaveric donors. ^[55] Although human leukocyte antigen (HLA) matching was performed, it usually was poor, and 13 patients in their series had lymphocytotoxic positive cross-matches.

Although a full discussion of the operative technique is beyond the scope of this article, a brief outline of the procedures of combined liver–small bowel transplantation and isolated small bowel transplantation is worthwhile (see Relevant Anatomy and Indications). Some details that bear discussion here were published by Abu-Elmagd et al. ^{[55, 53]} The University of Wisconsin solution was used for graft preservation. These investigators have preserved the donor enteric and celiac ganglia as a measure to decrease postoperative graft dysmotility.

Nontransplant operations require meticulous technique as well. The bowel must be handled gently and the blood supply guarded jealously.

Abdominal visceral organ procurement may begin with an attempt at GI tract sterilization by intragastric administration of a nonabsorbable antibiotic suspended in a cathartic solution. Proximal and distal abdominal aortic control is achieved at the aortic hiatus and caudal to the inferior mesenteric artery. The proximal aorta is clamped, and the distal aorta is cannulated.

Cold preservation solution is used to perfuse the abdominal viscera to be excised and transplanted. Drainage is provided by the creation of a venotomy in the suprahepatic inferior vena cava. The bowel is stapled proximally and distally. Other visceral vascular connections are divided and the graft specimen removed.

If the patient is to receive a transplant consisting of the liver and intestine, GI tract continuity is restored by proximal and distal anastomosis. Some authors have advised creation of proximal and distal stomas via limbs of intestine because prolonged intestinal decompression may be necessary in the early postoperative period.

Arterial blood supply is reestablished by anastomosis of a Carrel patch of the celiac axis and superior mesenteric artery to the aorta, or, if donor aorta is included, an aorto-aortic anastomosis is possible. Venous drainage of the intestine is intact to the liver in a combined hepatic-intestinal transplant.

Hepatic venous drainage can be accomplished by harvesting donor retrohepatic inferior vena cava with preservation of the donor hepatic veins distally. This is anastomosed to the recipient inferior vena cava circumferentially. Alternately, the donor inferior vena cava can be anastomosed to the recipient vena cava via an anterior venotomy. This anastomosis "piggybacks" the hepatic venous outflow onto the anterior surface of the recipient vena cava. This requires ligation of the caudal aspect of the donor inferior vena cava.

Venous outflow for the recipient's retained organs, such as the stomach, pancreas, and duodenum, can be established by anastomosis of the recipient portal vein to the donor vena cava or the donor portal vein.

When isolated intestinal grafts are used, a Carrel patch of the donor superior mesenteric artery is anastomosed to the recipient aorta. A long segment of donor superior mesenteric and portal vein is preserved for anastomosis to the recipient portal vein. GI tract continuity is reestablished as described above.

Postoperatively, fluid and electrolyte balance must be assured. (See Medical Therapy.) Calculated maintenance fluids are administered, and nasogastric, stool, stoma, and fistula outputs are recorded. These are replaced with fluids of similar makeup. Most frequently, this involves lactated Ringer solution. If large amounts of gastric secretions are lost, isotonic sodium chloride solution might be a more appropriate choice.

Most patients are maintained on parenteral nutrition initially. Enteral intake should be started as soon as possible, beginning with small amounts and gradually increasing. Several smaller feedings per day are usually advisable.

Transplant recipients are begun on immunosuppressive drug therapy. Standard immunosuppression regimens are based on tacrolimus and prednisone. Investigators at the University of Pittsburgh have used adjunctive drugs, such as cyclophosphamide, mycophenolate mofetil, and azathioprine, early in the postoperative period as well.

Both nontransplant and transplant patients can experience the typical postoperative complications of surgical patients in general. These include hemorrhage, wound complications, postoperative pulmonary dysfunction, renal failure, and pulmonary embolism, to name a few.

In nontransplant patients, the following postoperative complications may occur:

• Bowel obstruction
• Bowel necrosis
• Bowel dysmotility and dysfunction
• Anastomotic disruption
• Stasis of intestinal contents with or without bacterial overgrowth

Transplant recipients are subject to all the complications mentioned above. In addition, they may develop serious and sometimes lethal complications specifically related to transplantation and immunosuppression, such as the following:

• Acute rejection
• Chronic rejection
• Hepatic, portal, or mesenteric vein thrombosis
• Systemic sepsis with ordinary pathogens or opportunistic organisms (eg, cytomegalovirus)
• Lymphoproliferative disorders or malignancies

Patients with short-bowel syndrome require lifetime follow-up. Those on parenteral nutrition require frequent monitoring of serum chemistries; liver function tests; and vitamin, mineral, and trace element levels. ^[56] Patients should be weighed regularly after resolution of postoperative fluid flux to ensure that they are not losing weight on their nutritional regimen. Nitrogen balance studies can be performed but are cumbersome because of the need for 12- to 24-hour urine collection. Patients on specialized enteral nutrition can be monitored similarly.

Patients who have had nontransplant operations are monitored to assure that proper wound healing and bowel function are occurring. In addition, several of the measures described above can be applied to their postoperative care. It is important to confirm that these patients can ingest and absorb adequate amounts of protein and calories.

Patients who receive single or multiple organ transplants are monitored, and their cases are followed closely. The most dreaded postoperative complications that must be identified early include organ rejection, opportunistic infection, and development of immunosuppression-related malignancies. These patients may be monitored by all the measures mentioned above. In addition, immunosuppressant drug levels can be monitored.

The physician usually diagnoses acute rejection by endoscopically guided mucosal biopsies, and chronic rejection is diagnosed definitively by complete examination of resected grafts.

Transplant patients must also be monitored for evidence of graft-versus-host disease. Typically affected areas include the skin, GI tract, liver, and lungs.