During the immediate postoperative period, for up to two months, virtually all nutrients, including water, electrolytes, fats, proteins, carbohydrates, and all vitamins and trace elements are absorbed from the gastrointestinal (GI) tract poorly, unpredictably, or not at all [38]. Fluid losses via the GI tract are greatest during the first few days following massive small intestinal resection, and anal or stomal effluent frequently reaches volumes in excess of 5 L per 24 h. In order to minimize life-threatening dehydration, hypovolemia, hypotension, electrolyte imbalances, and other related potential problems, vigorous fluid and electrolyte replacement therapy must be instituted promptly and judiciously. Frequent measurements of vital signs, fluid intake and output, and central venous pressure, together with regular determinations of hematologic and biochemical indices, are mandatory in monitoring the patient during this period of rapid metabolic change and instability . All patients with short bowel syndrome exhibit some abnormalities in their liver profiles, and the vast majority of them experience at least transient hyperbilirubinemia [38]. This has been advocated by some to be secondary to the translocation of microorganisms and/or their toxins through the ischemic or gangrenous intestinal mucosa into the portal vein and thence to the liver [39, 40]. Others attribute the hyperbilirubinemia to impaired blood flow to the liver through the portal vein by as much as 50% as a result of greatly diminished mesenteric venous return secondary to the massive small bowel resection [41]. Still others attribute this phenomenon to a combination of both factors and/or other etiologies [42]. Broad spectrum anaerobic and aerobic antibiotic therapy should be instituted empirically and maintained for several days to one week following massive intestinal resection.

Typical patient management efforts during this period are directed toward achievement of four primary goals: fluid and electrolyte replacement, antisecretory/antimotility therapy, antacid therapy, and total parenteral nutrition. During the first 24–48 h, replacement therapy usually consists of 5% dextrose in lactated Ringer’s solution administered intravenously concomitantly with appropriate amounts of potassium chloride and/or acetate, calcium chloride and/or gluconate, magnesium sulfate, and fat- and water-soluble vitamins. If there is no evidence of sepsis, low salt human albumin (12.5–25 g) usually is added exogenously to the intravenous regimen every 8 h for the first 24–48 h postoperatively in order to maintain normal plasma albumin concentrations and normal plasma colloid oncotic pressure. It is the authors’ opinion and experience that maintenance of optimal intravascular colloid osmotic pressure with normal albumin and erythrocyte concentrations reduces intestinal mucosal edema and enhances fluid and nutrient absorption, while reducing losses as diarrhea. In patients with severe diarrhea, zinc losses can increase to as much as 15 mg/day, and appropriate aggressive, parenteral replacement is required [43].

Anti-acid therapy can reduce the increased tendency for peptic ulceration, which commonly occurs following massive small bowel resection. Antacids are given through a nasogastric tube, if one is in place, every 2 h in doses of 30–60 mL, and the tube is then clamped for 20 min before reapplying suction. Alternatively, or concomitantly, liquid sucralfate can be given by mouth or via the nasogastric tube in a dose of one gram every 6 h, clamping the tube for 20 min after each dose. To counteract the hypergastrinemia and associated gastric hypersecretion which follows massive small bowel resection in the majority of patients, an H₂ receptor blocker is infused intravenously [44]. The intravenous administration of 300–600 mg of cimetidine every 6 h can have a profound effect on reducing gastric acid and intestinal fluid production. Alternatively, ranitidine 150 mg can be given I.V. every 12 h, famotidine 20 mg can be given I.V. every 12 h, or an intravenous form of a proton pump inhibitor, pantoprazole, can be given daily in 40 mg doses. In selected short bowel patients, somatostatin analog (octreotide) has reduced fecal losses when administered in a dosage of 50–150 mcg I.V. or subcutaneously every 6 h [45, 46]. If the diarrhea persists despite these measures, an opiate can be prescribed. Preferably, codeine is given intramuscularly in doses of 60 mg every 4 h. Improvement in fluid and electrolyte management can also be achieved in selected patients with stomal access to a distal defunctionalized bowel loop by reinfusing the chyme from the proximal stoma into the distal bowel segment [47]. Later in the course of the postoperative period, when the patient is tolerating liquids by mouth, antimotility therapy can be achieved by giving loperamide 4–16 mg orally in divided doses daily, cholestyramine 4 g every four to 8 h, and/or diphenoxylate 20 mg every 6 h. Codeine 30–60 mg, paregoric 5–10 mL, or deodorized tincture of opium (DTO) 10–30 drops every 4 h orally can be used to impede bowel motility. The major advantages of DTO are that it is readily absorbed by the upper alimentary tract and that the patient’s bowel hypermotility and diarrhea can be titrated to tolerable therapeutic levels by adjusting the dosage up or down a few drops at a time to optimize dose effectiveness and to minimize undesirable side effects [7, 21].

By the second or third postoperative day, the patient’s cardiovascular and pulmonary status has usually stabilized sufficiently to allow TPN to be initiated [7, 21]. The average adult patient can usually tolerate 2 L of TPN solution daily administered by central vein. By titrating levels of plasma glucose and glycosuria, the daily nutrient intake can be increased gradually to desired levels or to patient tolerance. In a patient with diabetes mellitus, or in one who is glucose intolerant, crystalline regular human insulin is added to the TPN solution in dosages up to 60 units per 1000 calories as needed. Following an operation of the magnitude of massive small bowel resection, patients may require up to 3000 mL of TPN solution (about 3000 calories) per day initially for a few days to maintain nutritional and metabolic homeostasis. Supplemental fluid and electrolyte infusions may be necessary for several days or weeks to replace excessive losses as diarrhea. The patient is offered a clear liquid diet as soon as the postoperative condition is stabilized, and fecal output is controlled with antidiarrheal medications. It may take several days to several weeks before the patient is able to discontinue TPN support in favor of oral or enteral feedings. It is essential to provide adequate nutritional supplementation with TPN for as long as the patient requires such support to maintain optimal nutritional status. The TPN ration is reduced gradually in an equivalent reciprocal manner as oral intakes and intestinal absorption of required nutrients are increased. The patient’s diet is advanced slowly and gradually to a low lactose, low fat, high protein, high carbohydrate composition according to individual tolerances to the nutrient substrates and to the water volume and osmolality of the dietary regimen [7, 21, 48].

During the period of bowel adaptation from two months to 2 years postoperatively, the patient is allowed to consume increasing amounts of water, simple salt solutions, and simple carbohydrates [7, 21]. Various fruit and other flavorings can be added to 5% dextrose in lactated Ringer’s solution as a relatively inexpensive and practical oral nutrient and fluid replacement solution. Gradually, dilute solutions of chemically defined diets containing simple amino acids and short chain peptides are given as tolerated in increasing volumes and concentrations as bowel adaptation progresses toward a normal or near normal diet consisting of high carbohydrate, high protein, and low fat, and comprised of food most preferred by the patient as the next stage of nutritional rehabilitation. Alternatively, the major nutrients can be provided as required in commercially prepared modular feedings tailored to the needs of individual patients until ordinary food is well tolerated. All essential vitamins, trace elements, essential fatty acids, and minerals are initially supplied in the patient’s balanced intravenous nutrient ration. Subsequently, the oral diet may be supplemented most economically by short- and medium-chain triglycerides in the form of coconut oil, 30 mL two or three times daily; essential fatty acids as safflower oil, 30 mL two or three times daily; multiple fat- and water-soluble vitamins in pediatric liquid form, 1 mL twice daily; vitamin B₁₂, 1 mg intramuscularly every four weeks ; folic acid, 15 mg intramuscularly weekly; and vitamin K, 10 mg intramuscularly weekly. Some patients may require supplemental iron, which can be administered initially by deep intramuscular injection as iron-dextran according to the recommended patient-specific dosages schedule, or as an I.V. infusion after testing the patient for sensitivity [7, 21]. Alternatively, an oral liquid iron preparation can be given one to three times daily, while closely monitoring iron indices and liver function tests.

A strong tendency for patients with short bowel syndrome to develop metabolic acidosis usually requires the use of sodium bicarbonate tablets, powder, wafers, or liquid in doses of 8–12 g/day for as long as 18–24 months, but usually not for fewer than six months [7, 21]. It is often helpful to alternate the form of sodium bicarbonate prescribed in order to encourage maximal patient compliance. Because of the difficulty in absorbing adequate dietary calcium, supplemental calcium gluconate should also be prescribed as tablets, wafers, powder, or liquid in doses of 6–8 g/day. As bowel adaptation progresses, the doses of sodium bicarbonate and calcium gluconate can be decreased concomitantly or discontinued as restorative goals are attained. However, such oral supplements may be necessary for as long as two years or more in some patients in order to maintain homeostasis. Occasionally, on the other hand, a patient may become severely acidotic (pH 7.0–7.2) as a result of obviously copious diarrhea, but sometimes more subtly, and may require urgent or emergency intravenous infusion of sodium bicarbonate. Usually the patient responds promptly to the therapy within a few hours and without untoward sequelae. Rarely, calcium gluconate must be given intravenously as a supplement to correct recalcitrant hypocalcemia (<8.0 mg/dL). It is important to maintain normal serum albumin levels in patients with hypocalcemia. Dietary advancement and nutrient supplementation must obviously be individualized for each patient, and an effective nutrition support team can be very helpful in maintaining and monitoring these complex patients. When solid foods are given, they should be dry and followed 1 h later with isotonic fluids, rather than giving solids and liquids together at the same time. This practice is followed to minimize diarrhea and to improve nutrient absorption. Lactose intolerance should be anticipated and treated as required with a low lactose diet and/or lactase, 125–250 mg by mouth. Clearly, milk products should be avoided as much as possible if intolerance persists [7, 21].

As progress occurs during the bowel adaptation period of management of the short bowel syndrome, fat can be increased in the diet as tolerated, and supplementation with short- and medium-chain triglycerides and essential fatty acids may no longer be necessary [7, 21]. Serum-free fatty acid levels and triene:tetraene ratios are monitored periodically to determine the efficacy of treatment and the need for supplementation. Contrary to early reports, high fat diets apparently are comparable to high carbohydrate diets when evaluated in reference to calories absorbed, blood chemistries, stool or stomal output, urine output, and electrolyte excretions [47]. However, it has been suggested that enteral intake of fat should approach 50–100% greater than expected goals to compensate for malabsorbed nutrients [43]. Patients who cannot tolerate or utilize a normal oral diet should be given a trial of continuous administration of enteral formula. Low residue, polymeric, chemically defined, or elemental diets offer the putative advantage of high absorbability in the short bowel patient. However, some investigators have recently shown no differences in caloric absorption, stomal output, or electrolyte loss among elemental, polymeric, and normal diets in patients with short bowel syndrome [7, 21, 49–51].

Depending upon the results of periodic hematologic and biochemical studies, adjustments are made in the patient’s intake of sodium, potassium, chloride, and calcium [52]. Additionally, intermittent supplemental infusions of solutions containing magnesium, zinc, copper, and selenium may be required. As malabsorption and diarrhea become less troublesome, the vitamin and trace element requirements may be satisfied by multivitamin capsules, tablets, or chewable tablets containing therapeutic doses of vitamins or minerals, one dose twice daily. Relatively large amounts of magnesium, zinc, vitamin C, and vitamin B-complex can be administered in the form of several commercially available therapeutic vitamin and mineral preparations [7, 21, 38]. It is especially important to avoid thiamine deficiency (Wernicke’s syndrome).

In some patients, it may be necessary periodically to correct individual nutrient substrate deficiencies intramuscularly or intravenously for prolonged periods of time. Intermittent infusions of human serum albumin and packed erythrocytes may be required to treat recalcitrant hypoalbuminemia and anemia and to restore the plasma albumin level and the hematocrit to normal. Cholestyramine can be administered to counteract bile salt diarrhea if indicated, but intraluminal cholestyramine itself can cause or aggravate diarrhea. Fatty acid, electrolyte, trace element, vitamin, and acid–base imbalances must be promptly corrected enterally or parenterally as required when manifested clinically or by laboratory assessment. Serum vitamin B₁₂ levels must be monitored and its deficiency corrected immediately. Hyperoxaluria should be assessed regularly, and if documented, foods containing high levels of oxalate such as chocolate, spinach, celery, carrots, tea, and colas should be restricted [7, 21].

In patients with severe forms of short bowel syndrome, in whom little or no small intestine is present distal to the duodenum, or in whom the remaining small intestine has residual disease, hypermotility and recalcitrant or intractable diarrhea may require continuous long-term antimotility/antisecretory treatment with oral and/or parenteral forms and dosages of the previously described pharmaceutical agents. Additional oral medications which have been helpful in selected patients include omeprazole, 20 mg daily; propantheline bromide, 15 mg every 4–6 h; dicyclomine hydrochloride, 20–40 mg every 6 h; hyoscyamine sulfate, 0.125–0.250 mg every 4–6 h as needed [7, 21].

Long-term management of the short bowel syndrome can be accomplished successfully in most patients by conscientious attention to the principles and practices outlined previously. However, in a few patients who have undergone massive small bowel resection, total or supplemental parenteral nutrition must be provided in a continuous or cyclic manner for extended periods of time, and sometimes for life. The metabolic management and nutritional therapy of patients with the short bowel syndrome must be tailored specifically to each patient, and the clinical responses following massive intestinal resections depend upon many and varied factors. Patients with the short bowel syndrome pass through several stages of nutritional and metabolic support during their recovery, convalescence, and rehabilitation. Most of them can ultimately be maintained on a normal or near normal diet. However, depending upon the adaptability of their remaining bowel , they may have to settle for receiving their nutritional requirements by one or more of the following options:

Almost every patient with the short bowel syndrome eventually develops gallstones, most usually requiring cholecystectomy within two years following massive intestinal resection if the gallbladder had not been previously removed. Indeed, the high propensity of patients who have undergone massive intestinal resection to develop stones in their gallbladders has stimulated some physicians to advocate cholecystectomy prophylactically at the time of bowel resection [53]. However, gallstone formation in the common bile duct and elsewhere in the biliary tree is also increased in these patients even after cholecystectomy. Therefore, long-term surveillance with periodic abdominal ultrasonography may be useful in identifying and monitoring echogenic changes in the gallbladder and biliary tree in short bowel patients [7, 21].

Finally, some otherwise stable patients occasionally develop recalcitrant diarrhea secondary to colonization or bacterial overgrowth of the residual small bowel segment, requiring periodic stool culture and bacterial antigen studies followed by parenteral treatment with appropriate antibiotics [7, 21].

A rather extensive study was carried out initially to determine if growth hormone or nutrients, given alone or together, could enhance absorption from the small bowel after massive intestinal resection, especially in patients who continued to experience malabsorption and require long-term parenteral nutrition [54]. The effects of high carbohydrate, low fat diet, administered alone, or in combination with the amino acid, glutamine, and growth hormone were studied in 47 adult patients with short bowel syndrome, who had been dependent on TPN to some extent for an average of 6 years. The mean age of the patient was 46 years, and the mean residual small bowel length was 50 cm in those with all, or a portion, of the colon remaining, and 102 cm in those with no colon remaining. During the 28-day trial of therapy using this regimen, recombinant growth hormone was given by subcutaneous injection at a dose ranging from 0.03 to 0.14 mg/kg/day (average dose 0.11 mg/kg/day). Supplemental glutamine was provided by both the parenteral and enteral routes. The parenteral glutamine dosage averaged 0.6 g/kg/day, whereas a standard daily dose of 30 g glutamine was administered orally in six equal portions of 5 g mixed within a hypotonic cold beverage. In addition to the growth hormone and glutamine, all patients underwent extensive diet modification and nutritional education, the details of which have been reported extensively elsewhere [55]. Growth hormone was discontinued at the end of the four week protocol, and the patients were discharged home receiving only oral glutamine, 30 g/day, and the modified oral diet [7, 21].

The initial balance studies indicated improvement in absorption of protein by 39%, accompanied by a 33% decrease in stool volume output during the 28-day trial. In evaluation of the long-term results, averaging one year and extending as long as five years, 40% of those studied remained free of TPN; an additional 40% had demonstrated a reduction in their TPN requirements; and TPN requirements were unchanged in the remaining 20%. These changes had occurred in a subset of patients that had previously failed to adapt to the provision of enteral nutrients, and this therapy may offer an alternative to long-term dependence on TPN for some patients with severe short bowel syndrome. Subsequently, a more comprehensive clinical study of greater than 300 patients has been reported by the same group of investigators [56, 57]. However, growth hormone alone has not been shown to be beneficial consistently in other randomized, blinded, placebo-controlled, crossover studies, and the Bryne et al. study results have not been able to be reproduced by other investigators [58–60]. These conflicting data emphasize the need for further clinical studies to evaluate the effects of trophic agents in promoting, enabling, and/or enhancing intestinal adaptation [61]. Both growth hormone and glutamine are available for clinical use, but growth hormone generally is not used routinely or very often in attempts to enhance intestinal adaptation in patients with short bowel syndrome, primarily because of its high cost, untoward side effects, and questionable efficacy, which have supported both the cautious approaches among many clinicians, and the scrutiny and conservative attitudes by the Federal Food and Drug Administration related to the use of growth hormone for this purpose [58, 62–64]. The use of growth hormone has been limited largely because of concerns related to efficacy and the fact that only short-term use has been approved. Moreover, the effects of growth hormone on intestinal absorption in human beings are still unknown, whereas it appears to increase reabsorption of sodium in the distal nephrons, preventing pressure natriuresis and increasing extracellular volume [65]. On the other hand, it has been shown that patients with acromegaly have an increased risk of developing colonic neoplasia and adenomas although no increase in malignancy has been reported [66].

A multitude of growth factors other than growth hormone may be involved in the complex and multifactorial process of intestinal adaptation in patients with SBS following massive resections. Some of them include vascular endothelial growth factor (VEGF), hepatocyte growth factor, transforming growth factor-ß, epidermal growth factor, keratinocyte growth factor (KGF), insulin-like growth factor-1(IGF-1), cholecystokinin, gastrin, insulin, neurotensin, and glucagon-like peptide-2 (GLP-2) [63, 67]. GLP-2 is among the first of these factors to be evaluated in human beings with short bowel syndrome/intestinal failure (SBS/IF). GLP-2 is released from cells in the distal small bowel and the colon in response to ingestion of food, but this response is severely diminished in patients with SBS/IF, especially with ileal resection [68]. However, in patients with preserved colon, the meal-stimulated release of GLP-2 is enhanced. GLP-2 promotes intestinal epithelial growth by increased hyperplasia which may be further enhanced by increasing mesenteric blood flow [69]. GLP-2 also increases gastrointestinal transit time, which may be one of the mechanisms by which it decreases diarrhea [70]. Although native GLP-2 has resulted in less chronic dehydration and associated nephropathy together with a beneficial effect on bone health [71–73], these actions are limited by a very short half-life. Accordingly, a longer acting GLP-2 analog (Teduglutide) was created by substituting a glycine residue for alanine, which resulted in increased resistance to rapid enzymatic degradation [63].

About five years ago, a review article on the management options in the short bowel syndrome reported that administration of glucagon-like peptide-2 (GLP-2) to patients following major small bowel resection improved intestinal adaptation and nutrient absorption [74]. Based on data derived from multiple clinical studies in patients with SBS/IF, Teduglutide, an enzyme-resistant GLP-2 analog, had shown promise in preventing intestinal injury, restoring mucosal integrity, increasing villous height, enhancing intestinal absorptive function, reducing gastric emptying and secretion, and increasing lean body mass [75–80]. A prospective, multi-institutional, multi-national collaborative study was undertaken to determine if the parenteral nutritional support in patients with SBS/IF could be reduced by adding Teduglutide to the treatment regimen [77]. However, further studies and the completion of ongoing phase III trials were deemed necessary to determine the appropriate dosage (high vs. low) and length of treatment required for these patients to gain optimal benefits from the administration of this novel growth factor [74, 75]. In a subsequent 24-week, extremely complex, multi-national study of a very complicated group of 86 patients with SBS/IF (in fact, the largest prospective study ever carried out in this patient population), subcutaneous Teduglutide was shown to be safe and well tolerated; it facilitated reduction in the required volumes of parenteral nutrition; and it allowed patients to have some days free of parenteral nutrition [81]. Furthermore, Teduglutide administration could reduce malabsorption-related consequences (diarrhea, large stomal output, stomal problems, fecal incontinence, meteorism, abdominal pain), parenteral nutrition-related inconveniences (time spent connected to parenteral nutrition apparatus, social isolation, disturbed sleep, altered body image), and potentially life-threatening complications (catheter-related sepsis, central venous thrombosis, and SBS/IF-associated liver disease). Based on the findings of this study, Teduglutide could positively add to the limited treatment armamentarium of SBS/IF [81]. Teduglutide allows the clinician an additional option for patient management as an incremental improvement in the care of patients with SBS/IF [63]. It also has the potential to improve quality of life for patients with SBS/IF although a fully validated measure of quality of life in these patients remains to be developed. Finally, the development of longer acting analogs, as well as other growth factors, such as HGF and KGF, provides promises of future therapeutic advances in this vitally important area of SBS treatment and management [63].

A recent study has shown that the fecal microbiome of patients with SBS is significantly different from that of healthy controls when analyzed by metagenomics, and such changes in the intestinal microbiome of patients with SBS are thought to affect clinical outcomes significantly [82]. The changes may not only interfere with, or delay the advancement of, enteral diet, but may also predispose patients to bacterial translocation, bacteremia, and liver disease. SBS patients are thought to be more susceptible to changes in gut microbial compositions due to intestinal dysmotility and/or lack of adequate anatomic safeguards, such as the ileocecal valve. In a small study, the fecal microbiome of nine children with SBS was different from that of eight healthy control children. Stool from the SBS patients had significantly greater abundance of Gammaproteobacteria and Bacilli, and decreased abundance of Ruminococcus. Differences in the composition and function of intestinal microbiomes in children with SBS may affect bowel physiology and these findings may provide new prospects for opportunities for intestinal rehabilitation and clinical management. Future studies including whole-genome “shotgun” metagenomics of fecal samples and longitudinal sampling of children with SBS are also likely to provide additional insights into the potential role of the microbiome in intestinal adaptation and barrier function, such as bacterial translocation, in children with SBS [82].