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Indications for specific therapy in the rehabilitation of patients with the short-bowel syndrome
Best Practice & Research Clinical Gastroenterology Vol. 17, No. 6, pp. 895 –906, 2003 doi:10.1053/ybega.2003.419, www.elsevier.com/locate/jnlabr/ybega
2 Indications for specific therapy in the rehabilitation of patients with the short-bowel syndrome Douglas W. Wilmore*
MD
Department of Surgery and the Laboratories for Surgical Metabolism and Nutrition, Brigham and Women’s Hospital, Harvard Medical School, Huntington Avenue, 75 Francis St, Boston MA 02115, USA
Diarrhoea, malabsorption and malnutrition characterize the short-bowel syndrome. Following the initial intestinal resection, complications such as fistulas and intra-abdominal abscesses may occur, but these usually resolve with appropriate surgical care. All residual intestine should be placed in continuity before serious attempts at rehabilitation with oral feedings are initiated. Small hourly oral feedings composed of food items high in complex carbohydrate and low in fat are started when appropriate and the diet is gradually increased as intestinal adaptation occurs. The goal during this process is to prevent diarrhoea and allow the formation of semiformed stools. With time, parenteral nutrition (PN) can be reduced, and the time required depends on both length of residual bowel and the particular anatomy involved—for example, the presence or absence of the colon. A programme of optimal diet plus growth hormone (0.1 mg/kg) and oral glutamine (30 g/day) enhances the adaptive process and allows many patients independence from PN. However, those with extremely short segments of jejuno-ileum (, 50 cm) and no colon have excessive fluid and electrolyte losses, and intestinal transplantation may be the only therapy which allows such patients to be independent of PN. Key words: short-bowel syndrome; intestinal rehabilitation; growth hormone; glutamine.
The short-bowel syndrome (SBS) is a malabsorptive disorder characterized by loss of intestinal length. The adult has approximately 600 cm of jejuno-ileum, and loss of twothirds or more of the small bowel is defined as the SBS (a remnant small bowel of , 200 cm). Massive intestinal resection is often required following thrombosis of the mesenteric vessels, severe inflammatory bowel disease, abdominal trauma, congenital abnormalities, and volvulus. Following resection, the patient experiences diarrhoea, malabsorption, fluid and electrolyte abnormalities and progressive malnutrition, demonstrated by both macro and micronutrient deficiencies. With the improvements in diagnostic techniques, anaesthetic and surgical care and post-operative support, patients usually survive the acute catastrophic events associated with massive intestinal resection and are discharged from the acute care setting. Their overall rehabilitation is dependent on a variety of factors, including age, * Tel.: þ 1-617-732-5280; Fax: þ1-617-732-5506. E-mail address: [email protected] 1521-6918/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
896 D. W. Wilmore
co-morbidities, patient motivation and family support, as well as the knowledge and experience of the health care providers. Those adults between 20 and 50 years of age without associated disease who have normal intestinal mucosa in their remnant intestine have the best opportunity to respond to current therapy and return to a nearnormal productive life. The purpose of this chapter is to present what evidence exists to aid decisionmaking concerning various choices of therapy useful in the rehabilitation of these patients. Because the SBS is relatively rare (probably only about 15 000 patients exist in the USA, a population of over 284 000 000 people) and few individuals are cared for in any one clinic, data derived from large randomized trials are generally lacking. Rather, studies in small heterogeneous groups of patients have been reported, and variations in primary diseases and residual anatomical structures have not allowed definitive conclusions to be made regarding various forms of therapy. In addition, case reports and observational studies are also available for review, but the value of this information is also limited. Our clinical experience and randomized trials in the care and study of more than 500 patients with SBS will be utilized to place the available information on decision-making in the appropriate clinical perspective.
POST-OPERATIVE CONSIDERATIONS AND THE INITIAL ENTERAL DIET Post-operative complications are common in patients following massive intestinal resection; re-exploration and further resection of necrotic bowel are frequently necessary, and the presence of intra-abdominal abscesses and fistula are common. The surgical team, often working in co-operation with the invasive radiology service, can usually resolve these immediate post-operative problems. If the patient has bowel, which has not been placed in continuity of the nutrient stream, an additional operation should be performed in a stabilized patient free of complications. Patients following massive intestinal resection are frequently quite ill in the perioperative period, and caregivers are often hesitant to subject a recuperating individual to subsequent operative procedures. Often, home discharge is one technique utilized to relieve the surgeon of the anxiety associated with the care of a patient who has sustained a catastrophic illness. However, if the patient is to progress through a programme of rehabilitation, then closing ostomies and placing all remaining bowel in continuity is a key undertaking to initiate this process. This important step early in the initial or a subsequent early hospitalization is necessary in order to maximize exposure of all of the available intestinal surface area to enteral nutrients and thereby enhance intestinal adaptation and maximize absorption.1,2 Enteral nutrient exposure is necessary to stimulate bowel adaptation, and attention should be specifically directed toward optimizing enteral feedings. Again, it should be emphasized that an additional operation should be undertaken only in a patient who has recovered from the initial resection and the risk of the procedure is low. If the initial surgical team is reluctant to operate on the patient, then a referral to a centre which specializes in complex gastrointestinal surgery is appropriate. Oral food intake is initiated as soon as the patient accepts meals and feeding is not contraindicated by the patient’s medical condition. Tube feedings are rarely used; rather, small hourly feedings of no more than 600 kcal/day given along with 30 ml of fluid/hour are provided. Foods high in complex carbohydrate, low in fat and high in protein are initially selected and rice, baked potatoes, and pasta served with chicken,
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fish or lean meat are the mainstay of this initial diet. Simple sugars should be avoided because of their osmotic contribution, which augments intestinal transit and diarrhoea. The goal of this approach is to control dietary intake and thereby prevent or control diarrhoea. Anti-motility agents should be initiated and, on occasion, anti-nausea medication is utilized. It usually takes weeks and, on occasion, months, for patients with SBS to tolerate this diet, but with bowel adaptation there is passage of semiformed stools indicating that the quantity of the diet can be gradually increased over time. In patients with ostomies, adaptation is characterized by a gradual decrease in the volume of the effluent. Practice points † all bowel should be placed in continuity before intestinal rehabilitation is started † the initial oral diet and fluid intake should be small, frequent feedings containing high complex carbohydrate and low-fat to prevent initial episodes of diarrhoea
SELECTION OF THE FINAL ENTERAL DIET The final enteral diet should be based on the anatomy of the retained bowel the presence or absence of a colon and the ileum. The ileum is important because it is a major site for the absorption of fat and fat-soluble vitamins, including vitamins A and D. In addition, the ileum is relatively efficient in water absorption. Consequently, resections involving only jejunum often result in little diarrhoea, and the concerns of malabsorption of fat and fat-soluble vitamins are not as great as if a comparable resection was performed removing the ileum. In addition to the colon’s importance in absorbing water and electrolytes, the large intestine plays a unique role in the patient with short bowel for it serves as a fermentation chamber where bacteria metabolize unabsorbed carbohydrate and, to lesser extent, protein. 3 The byproducts of this process (short-chain fatty acids) serve as fuels for the colon and other more distant tissue. While discussed in more detail elsewhere (see pages XXX), patients with a portion of colon in continuity should receive a high-carbohydrate, low-fat diet, while those with small bowel ostomies may take a diet containing more fat (Table 1). Because malabsorption exists in all individuals, the patients must become hyperphagic and consume 25 – 75% more macronutrients than usually required if enteral autonomy is to be expected. This goal is usually easily achieved in previously overweight individuals who enjoy eating, but patience and constant coaching are required in slender, fastidious individuals who have a habitually limited food intake.
Practice points † a six-feeding diet high in complex carbohydrate and low in fat should be provided to patients with a portion of colon in continuity † a more balanced diet can be provided to patients with ostomies
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Table 1. Suggested diets for patients with the short-bowel syndrome.
Carbohydrate (% of diet) Composition
Fat (%) Protein (%) Fibre Oxalates Fluid
Patients with colon
Patients without colon
60
50–55
Complex carbohydrate, no or minimal simple sugars 20 –25 15 –20 Provided as food fibre Low* To insure a urinary output of .1200 ml/day
25–30 15–25 Fibre minimized No special requirement May require isotonic fluids with salt added to accommodate ostomy losses
PARENTERAL NUTRITION—WHEN TO START AND WHEN TO STOP Intravenous (IV) support is required during the post-operative period, and because enteral feedings are initially limited, parenteral nutrition (PN) is usually initiated. The initial formulation should contain enough volume to insure hydration and adequate electrolyte replacement. Some calories (including fat emulsions containing essential fatty acids), adequate protein, vitamins, and trace elements should all be administered. A hypocaloric diet is initially safe and effective for individuals who are overweight4; even in normal weight individuals, the calorie load can be calculated to supplement enteral intake. Such a parenteral formulation usually does not suppress appetite, and with time the IV nutrition can be cycled and administered at night and enteral feedings are provided during the day. In our practice, we have enhanced adaptation in many individuals over the immediate post-operative period by administering growth factors, and therefore, during this time we initially rely on PICC lines, placed in the patient’s arms and directed into the superior vena cava, as an early means of parenteral access. Placement of this line does not require an operation and it is frequently removed at the time of discharge if sufficient gut adaptation has taken place. If a more permanent central venous catheter is required for home PN, a central indwelling line is placed shortly before discharge. Dependence on parenteral support is usually related on the length of the residual bowel and the ability of the patient to take enteral feedings. Clinical experience teaches that patients with , 50 –70 cm jejuno-ileum anastomosed to a portion of colon or those with , 100 –140 cm small bowel and no colon (an ostomy) will require long-term parenteral therapy, possibly for life. 5,6 Thus, a central line for nutrient infusion may become a life-line for long-term survival of these individuals; attention must be directed to appropriate line care in order to minimize potential complications and to ensure IV access. In patients with slightly longer segments of small bowel, PN is a temporary means of support until adaptation has occurred and until enteral feedings are adequate
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Table 2. Estimated length of time required for parenteral nutrition depending on bowel anatomy. Presence (þ ) Length of small or absence (2) bowel (cm) of colon Time on PN 80 –150 50 –70 40 –70 ,60 10 –30
þ or 2 þ þ 2 þ or 2
1–6 months 1–6 months 6–12 months Permanent Permanent
and can sustain the individual (Table 2). 7 The time necessary for adaptation appears to be greatly reduced with the use of growth factors. By monitoring body weight, urine and stool output and concentrations of serum electrolytes and indices of renal function, gradual weaning from PN is possible with time.
Practice points † parenteral support is usually required following an operation, and IV support can gradually be converted to include the provision of all essential nutrients administered by vein † PN should serve as a supplement to enteral feedings, not become the principal means to sustain nutrient intake † central venous access is life-saving in some individuals, and care should be taken to prevent central venous thrombosis and catheter infection † many patients can be weaned from parenteral support with time, and predictions of the duration of IV support can be made in the adult based on small bowel length. Alternatively, the use of growth factors appears to accelerate this process
BOWEL REHABILITATION—WHO WILL BENEFIT? Bowel rehabilitation is an approach to patients with SBS which emphasizes an appropriate diet and usually utilizes specific nutrients and growth factors to enhance intestinal absorption. Over the past 20 years, factors, which regulate intestinal mucosal cell turnover, have been extensively studied. Growth factors such as growth hormone (GH), insulin-like growth factor-1, epidermal growth factor and glucagon-like peptide-2 (GLP-2) are a few of the many important regulators controlling gut growth, but other factors such as the amino acid glutamine (Gln), specific fatty acids, bile salts, interleukin 11 and other substances are also important. 8 With the biosynthesis of GH and its availability in the 1980s, we initiated a programme to study the impact of available trophic factors on intestinal absorption in patients with SBS. Encouraged by findings in animal investigations9,10 and preliminary patient studies11, we initiated a phase I study to determine the safety and efficacy of this
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approach. These results suggested that about 40% of the PN-dependent patients studied were able to be weaned from IV feedings and remain independent of IV support during the 3– 5 years of follow-up. 12 In a prospective randomized double-blind multicentre phase III clinical trial, we evaluated the safety and efficacy of GH and Gln, given alone or in combination to 41 PN-dependent patients. 13 Eligible patients met the following conditions: male or female between 18 and 75 years of age; body mass index (BMI) . 17; small intestinal length , 200 cm (as determined from the operative report); the ability to ingest solid food, but requiring . 3000 PN calories/week; have acceptable liver and kidney function (a serum bilirubin level less than three times normal and a serum creatinine , 3 mg/dl) and have normal or compensated and stable hypertension and/or cardiovascular disease. The patients had to have undergone bowel resection at least 6 months prior to the study, have an intact stomach and duodenum and have , 3 l stool output/day. In addition, one of the following criteria was required: (1) . 30% of colon anastomosed to . 15 cm jejunumileum or (2) , 30% colon anastomosed to $ 90 cm jejunum-ileum. Exclusion criteria included a BMI . 28; pregnancy or lactation; a history of cancer within 5 years; chronic infection; neurological disorder, mental debility or a history of psychiatric eating disorder or drug of alcohol abuse; sustained hypertension ($ 160/100 mm Hg); secretory bowel disease (a stool output . 800 ml/day with no oral intake); diabetes mellitus; hypoxaemic pulmonary disease (resting pAO2 # 75 Torr); unstable ischaemic heart disease or uncompensated cardiac failure; ingestion of glucocorticoids $ 10 prednisone or equivalent; the use of immunosuppresant therapy; a history of carpal tunnel syndrome; the use of other investigational drugs # 30 days before study entry and the previous administration of GH or other growth factors to enhance intestinal absorption. Those subjects who met these criteria and were interested in the study underwent a complete history and physical examination and appropriate blood testing. The operative report of the previous resection was obtained and the history of body weight over the past 2 months was reviewed. Forty-one patients were eligible for study and all became study participants. The study was a randomized, double-blind, controlled, parallel-group multicentred phase III clinical trial. All participants were admitted to an assisted living facility for 6 weeks and were monitored by physicians, nurses, and dieticians. The initial 2 weeks was a baseline period, which allowed observation, stabilization, and initiation of optimal nutritional support (both oral diet and parenteral support). The subjects received an individualized enteral diet low in fat (20 –30%) and high in complex carbohydrate (60%) adjusted to the subject’s requirements. The meals were provided as six feedings throughout the day. The ingestion of simple sugars was discouraged. During the first week 3-day meal plans were designed and provided on a rotational basis throughout the study. A minimal level of oral fluid intake was determined and fluid ingestion was also encouraged and recorded throughout the study. At the end of this 2-week period, the nutritional therapy was continued and the subjects were randomized to receive one of three types of therapy: 1. oral Gln (30 g/day in divided doses) plus subcutaneous GH placebo injections; 2. oral Gln placebo (30 g/day in divided doses) plus subcutaneous GH (0.1 mg/kg); 3. oral Gln plus subcutaneous GH at the doses outlined above. The first group, which represented the effects of optimal dietary intake, served as a control group for the GH-alone and co-therapy groups. The random allocation to
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the groups was in the ratio of 1:2:2, thus resulting in a final sample size of nine in the control group, 16 in the GH group and 16 in the GH-plus-Gln group. During the next 4 weeks, the assigned treatment was provided daily and the patients were monitored by recording daily body weight, vital signs, symptoms and complaints. Oral intake and volume of urine and stool were also measured. Based on an algorithm that utilized this data, IV feedings were adjusted to accommodate for enteral absorption. After the conclusion of the 4-week inpatient study period, the patients were discharged on the enteral and parenteral diets that they received on the last week on therapy. The patients were followed as outpatients for the next 3 months. The GH was not administered during this time, but the Gln or Gln placebo was taken daily. A followup visit was performed on the last week of the 18-week study, and the final physical examination, body weight, nutritional history and blood studies were obtained at this time. The primary study endpoint was the change in weekly PN volume measured on week 2 (the second week of the baseline period) and compared with week 6 (the last week of the treatment period). Secondary end points included the change in weekly caloric content and frequency of PN administration/week. After 4 weeks of therapy, the reduction in PN volume and calories was determined as well of the frequency of PN infusion (Table 3). All subjects demonstrated a reduction in PN support, with the combination of GH and oral Gln treatment resulting in a greater reduction in PN volume, calories, and frequency when compared with GH or Gln given alone. Upon discharge there was some need to increase PN administration in selected patients but the response pattern remained the same as the initial response at the 18-week follow-up period. Smaller studies in patients with SBS have administered GLP-2 and reported enhancement in body composition related to this agent.14 The specific use of this growth factor in the rehabilitation of PN-dependent patients has not as yet been reported. How are patients selected who may have the best chance of responding to specific growth factor rehabilitative therapy? To address this issue, we prospectively studied 49 stable PN-dependent adult patients with short bowel.15 Patients with secretory diarrhoea (. 800 ml stool or ostomy loss while taking nothing by mouth over a 24 hour period) and those who had a history of cancer within 5 years of admission were
Table 3. Data from the randomized, multicentre, double-blind trial (13) showing the decrease in weekly PN requirements (mean þ SD).
Group Diet þ Gln Diet þ GH Diet þ GH þ Gln a b
n¼9 n ¼ 16 n ¼ 16
PN volume (l)
PN calories (kcal)
PN frequency (infusions/week)
3.8 ^ 2.4 5.7 ^ 4.0a 7.7 ^ 3.3b
2633 ^ 1341 4308 ^ 1870a 5751 ^ 2082b
2.0 ^ 0.9 3.0 ^ 1.8a 4.2 ^ 1.4b
GH ¼ growth hormone; Gln ¼ Glutamine. P , 0:05: P , 0:001; when compared with Diet þ Gln group.
902 D. W. Wilmore
Table 4. The effect of growth hormone, glutamine and diet on outcome.
Length of small bowel (cm) Number Bowel length (cm) Off PN [# (%)] Reduced PN No change
Patients with a portion of colon
Patients with no colon
.70 8 122 5 (63) 3 (38)c 0
12 99 4 (33)b 6 (50) 2 (17)
,70 29 28 11 (38)a 16 (55) 2 (7)
a
Seven of these patients has ,35 cm of jejunum-ileum. All of these patients had .100 cm of jejunum-ileum. c Two of these patients had Crohn’s disease and the third had radiation enteritis. b
excluded from the study. All subjects underwent a month of inpatient therapy during which they were monitored and received an optimal diet, and GH and glutamine, as previously described. 11 The ability to remove patients from PN was related to bowel anatomy and, to a lesser degree, their primary diagnosis (Table 4). In patients with a portion of colon in continuity, about two-thirds of those with jejunoileal segments . 70 cm could be weaned from PN. As length of the residual small bowel diminished so did the success of this therapy. In the patients with , 70 cm of small bowel and colon, 38% of individuals were removed from PN. It is notable that seven of these individuals had , 35 cm of the jejunoileal segment remaining. Patients who most frequently failed to respond to this therapy had mucosal disease—Crohn’s disease or radiation enteritis—as the cause of their bowel resections. Four of the 12 patients with no colon became free from PN, but it is notable that all of these individuals had . 100 cm of remnant small bowel. Patients with shorter segments and ostomies remained PN-dependent, even thought the IV volume could be reduced in about 50% of these individuals. Thus, in patients with a portion of colon, the response to this form of intestinal rehabilitation is variable depending on small bowel length (Figure 1). However, many patients adapt following this form of therapy—we care for about a dozen patients with , 15 cm of jejuno-ileum anastomosed to colon who have been free of PN for years. Two of the women in this group have conceived, carried their babies to term and had normal deliveries. Other patients are able to reduce PN requirements, which enhances the individual’s quality of life. 16 Thus, in the group of patients with a portion of colon in continuity, a rehabilitation programme should generally be considered before contemplating a referral of the patient for intestinal transplantation. This is particularly true as new additional therapies that enhance bowel adaptation become available. In contrast, patients with very short segments of small bowel (, 50 cm) who have no colon have very large fluid losses which require parenteral replacement therapy. 17 The possibility of intestinal transplantation should be considered in these individuals, for no rehabilitation programme available at this time can wean such patients from parenteral therapy.
Specific therapy in rehabilitation 903
Body Weight (kg)
90
Low probability 50% of adaptation probability
High probability of being free of TPN after treatment with GH, GLN + diet
80
High probability of adaptation with short term TPN
70 60 50 40 30
0
20
40
60
80
100
Jejunal-ileal Length (cm) Figure 1. This chart uses probabilities to predict the success of weaning from parenteral nutrition, a patient with the short-bowel syndrome and a portion of the colon in continuity. To determine the outcome for an individual patient, locate the point at which bowel length and body weight cross. The area identified will describe the predicted outcome. Reproduced from Wilmore DW and Byrne TA. Approach to the patient with short-bowel syndrome. In Wolfe MM (ed). Therapy of Digestive Disorders, p 563. Philadelphia: Saunders, 1999.
Practice points † bowel rehabilitation which enhances intestinal adaptation is possible in patients utilizing an optimal diet, glutamine and GH † approximately 40% of PN-dependent patients become free of IV support over the long-term following such a programme † patients with a portion of colon represent appropriate candidates for such therapy. Small bowel length is the next predictor of success † in patients with no colon and small bowel ostomies and short intestinal segments (, 50 cm) intestinal transplantation at this time should be considered as the only therapy available to remove such individuals from PN
INDICATIONS FOR INTESTINAL TRANSPLANTATION Transplantation of the intestinal tract, with or without other visceral organs, has become more popular in recent years, given the poor outlook for PN-dependent patients with SBS.18 The international intestinal transplant registry reported the results from 273 transplants in 260 patients who received intestinal grafts19; 59% of the group received multiorgan grafts. In addition to a segment of small bowel, a liver was transplanted to replace the organ that was irreversibly damaged because of PN and other conditions associated with short bowel. Isolated small-bowel transplants, with or without colon, were reported in 41% of recipients; 1 year actuarial patient survival was 69% and graft survival was 55%. Thus, this procedure should not be viewed as a low-risk approach. In addition to the patients with end-stage liver disease, there may be other indications (relative or absolute) to consider in exploring this treatment option with
904 D. W. Wilmore
a patient. This is particularly true in individuals who do not have IV access (a rarity), or those who have life-threatening complications associated with PN (severe liver dysfunction, recurrent sepsis including fungaemia, etc.). Those patients with extremely short segments of jejunum-ileum and no colon have to this point in time not been able to be weaned from PN with current rehabilitation programmes, and intestinal transplantation should be discussed with these individuals as a treatment option.
Research agenda † intestinal transplantation is evolving, and this possibility should be explored with those eligible patients with no colon and short segments of small bowel (, 50 cm) † other patient groups to be considered are those who fail rehabilitation programmes and have life-threatening complications associated with PN, or those with irreversible liver disease † much research remains to be performed in this field. Research animals (particularly rodents) have been used as models for this syndrome, but their adaptive response is characterized by mucosal hypertrophy, which has not been observed in the human condition.20,21 This emphasizes the need for patient studies that require multicentre trials. Such investigations should be based in centres with interest and expertise in intestinal failure, and there are now in the USA about six of these centres of excellence. Such studies should include the evaluation of additional growth factors, given individually and in combination, to enhance bowel adaptation. The mechanisms by which Gln (and other nutrients) augment these responses need to be explored. Re-treatment or periodic treatment with growth factors may be necessary in some individuals, and this effect along with the dosage used and frequency of treatment should be studied. Small bowel segments are usually transplanted without colonic segments, and protocols need to be established which allow safe transplantation of large bowel, in order to evaluate its effect on residual function of the small intestine † while animal studies may be helpful, studies should be performed in humans with this condition † combinations of growth factors and nutrients should be tested in humans to determine the optimal therapy to enhance intestinal adaptation † studies should be performed transplanting colon along with small bowel in order to determine the role of the large bowel in intestinal function
SUMMARY The SBS occurs following massive intestinal resection and is a devastating event for patients. Diarrhoea, malabsorption, and malnutrition are the major symptoms. However, by initially supporting the patient with parenteral feedings and providing appropriate enteral feedings and gradually increasing oral intake, adaptation of the intestinal tract occurs. This response is characterized by an increase in intestinal absorption. Depending on the length of the residual bowel, the patient may become independent of parenteral nutritional support. This process is enhanced in selective
Specific therapy in rehabilitation 905
BOWEL REHABILITATION
FOLLOW UP
SHORT TERM TPN
LONG TERM TPN
BOWEL RESECTION
BOWEL TRANSPLANTATION Figure 2. A general care map that can be utilized in the treatment of patients with the short-bowel syndrome. The initiation of bowel rehabilitation in the immediate post-operative period has greatly shortened nutritional support and at times eliminated the need for long-term home parenteral nutrition. Reprinted with permission from the American Society for Parenteral and Enteral Nutrition (ASPEN.) from the following: Wilmore DW. Growth factors and nutrients in the short-bowel syndrome. Journal of Parenteral and Enteral Nutrition (JPEN) 1999;23:S119, Figure 1. ASPEN does not endorse the use of this material in any other form than its entirety.
individuals with an appropriate diet and the administration of GH and glutamine (Figure 2). Other growth factors will undoubtedly be successfully used in this process as more clinical data become available. However, some patients with very short segments of jejuno-ileum and no colon have such large fluid and electrolyte losses that small-bowel transplantation may be the only therapeutic approach to achieve enteral independence and reverse intestinal failure in these individuals.
REFERENCES 1. Levin GM, Daren JJ, Steiger E et al. Role of oral intake in maintenance of gut mass and disaccharidase activity. Gastroenterology 1974; 67: 975–982. 2. Feldman EJ, Dowling RH, McNaughton J et al. Effect of oral versus intravenous nutrition on intestinal adaptation after small bowel resection in the dog. Gastroenterology 1976; 70: 712–719. 3. Nordgaard I, Hansen BS & Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994; 343: 373–376. 4. Dickerson RN, Posato EF & Mullen JL. Net protein anabolism with hypocaloric parenteral nutrition in obese stressed patients. American Journal of Clinical Nutrition 1986; 44: 747–755. 5. Dudrick SJ, Latifi R & Fosnocht DE. Management of the short bowel syndrome. Surgery Clinics of North America 1991; 71: 625–643. 6. Rombeau JL & Rolandelli RH. Enteral and parenteral nutrition in patients with enteric fistulas and short bowel syndrome. Surgery Clinics of North America 1987; 67: 551–571. * 7. Gouttebel MC, Saint-Aubert B, Astre C & Joyeux H. Total parenteral nutrition needs in different types of short bowel syndrome. Digestive Diseases and Sciences 1986; 31: 718 –723. 8. Drucker DJ. Epithelial cell growth and differentiation. I. Intestinal growth factors. American Journal of Physiology 1997; 273: G3–G6. * 9. O’Dwyer ST, Smith RJ, Hwang TL & Wilmore DW. Maintenance of small bowel mucosa with glutamineenriched parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1989; 13: 579–585. * 10. Ulshen MH, Dowling RH, Fuller CR et al. Enhanced growth of small bowel in transgenic mice over expressing bovine growth hormone. Gastroenterology 1993; 104: 1205– 1208. * 11. Byrne TA, Persinger RL, Young LS et al. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Annals of Surgery 1995; 222: 243–254. * 12. Wilmore DW, Lacey JM, Soultanakis RP et al. Factors predicting a successful outcome after pharmacologic bowel compensation. Annals of Surgery 1997; 226: 288–292.
906 D. W. Wilmore * 13. Byrne TA, Lautz D, Iyer K et al. Recombinant human growth hormone (rhGH) reduces parenteral nutrition (PN) requirements in patients with the short bowel syndrome: a prospective, randomized, double-blind, placebo-controlled study. Journal of Parenteral and Enteral Nutrition 2003; . in press. 14. Jeppesen PB, Hartmann B, Thulesen J et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 2001; 120: 806 –815. * 15. Byrne TA, Nompleggi DJ & Wilmore DW. Advances in the management of patients with intestinal failure. Transplantation Proceedings 1996; 28: 2683– 2690. 16. Rovera GM, Anderson S, Camelio M et al. Enhancing outcome in patients receiving long term tpn. Clinical Nutrition 2000; 19: 2. 17. Nordgaard I, Hansen BS & Mortensen PB. Importance of colon support for energy absorption as smallbowel failure proceeds. American Journal of Clinical Nutrition 1996; 64: 222– 231. 18. Van Gossum A, Vahedi K, Abdel-Malik et al. Clinical, social and rehabilitation status of long-term home parenteral nutrition patients: results of a European multicenter survey. Clinical Nutrition 2001; 20: 205–210. 19. Grant D. Intestinal transplantation: 1997. Report of the International Registry. Intestinal Transplant Registry. Transplantation 1999; 67: 1061–1064. 20. Porus RL. Epithelial hyperplasia following massive small bowel resection in man. Gastroenterology 1965; 48: 753–757. 21. O’Keefe SJD, Haymond MW, Bennett WM et al. Long-acting somatostatin analogue therapy and protein metabolism in patients with jejunostomies. Gastroenterology 1994; 107: 379 –388.
2 Indications for specific therapy in the rehabilitation of patients with the short-bowel syndrome Douglas W. Wilmore*
MD
Department of Surgery and the Laboratories for Surgical Metabolism and Nutrition, Brigham and Women’s Hospital, Harvard Medical School, Huntington Avenue, 75 Francis St, Boston MA 02115, USA
Diarrhoea, malabsorption and malnutrition characterize the short-bowel syndrome. Following the initial intestinal resection, complications such as fistulas and intra-abdominal abscesses may occur, but these usually resolve with appropriate surgical care. All residual intestine should be placed in continuity before serious attempts at rehabilitation with oral feedings are initiated. Small hourly oral feedings composed of food items high in complex carbohydrate and low in fat are started when appropriate and the diet is gradually increased as intestinal adaptation occurs. The goal during this process is to prevent diarrhoea and allow the formation of semiformed stools. With time, parenteral nutrition (PN) can be reduced, and the time required depends on both length of residual bowel and the particular anatomy involved—for example, the presence or absence of the colon. A programme of optimal diet plus growth hormone (0.1 mg/kg) and oral glutamine (30 g/day) enhances the adaptive process and allows many patients independence from PN. However, those with extremely short segments of jejuno-ileum (, 50 cm) and no colon have excessive fluid and electrolyte losses, and intestinal transplantation may be the only therapy which allows such patients to be independent of PN. Key words: short-bowel syndrome; intestinal rehabilitation; growth hormone; glutamine.
The short-bowel syndrome (SBS) is a malabsorptive disorder characterized by loss of intestinal length. The adult has approximately 600 cm of jejuno-ileum, and loss of twothirds or more of the small bowel is defined as the SBS (a remnant small bowel of , 200 cm). Massive intestinal resection is often required following thrombosis of the mesenteric vessels, severe inflammatory bowel disease, abdominal trauma, congenital abnormalities, and volvulus. Following resection, the patient experiences diarrhoea, malabsorption, fluid and electrolyte abnormalities and progressive malnutrition, demonstrated by both macro and micronutrient deficiencies. With the improvements in diagnostic techniques, anaesthetic and surgical care and post-operative support, patients usually survive the acute catastrophic events associated with massive intestinal resection and are discharged from the acute care setting. Their overall rehabilitation is dependent on a variety of factors, including age, * Tel.: þ 1-617-732-5280; Fax: þ1-617-732-5506. E-mail address: [email protected] 1521-6918/03/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.
896 D. W. Wilmore
co-morbidities, patient motivation and family support, as well as the knowledge and experience of the health care providers. Those adults between 20 and 50 years of age without associated disease who have normal intestinal mucosa in their remnant intestine have the best opportunity to respond to current therapy and return to a nearnormal productive life. The purpose of this chapter is to present what evidence exists to aid decisionmaking concerning various choices of therapy useful in the rehabilitation of these patients. Because the SBS is relatively rare (probably only about 15 000 patients exist in the USA, a population of over 284 000 000 people) and few individuals are cared for in any one clinic, data derived from large randomized trials are generally lacking. Rather, studies in small heterogeneous groups of patients have been reported, and variations in primary diseases and residual anatomical structures have not allowed definitive conclusions to be made regarding various forms of therapy. In addition, case reports and observational studies are also available for review, but the value of this information is also limited. Our clinical experience and randomized trials in the care and study of more than 500 patients with SBS will be utilized to place the available information on decision-making in the appropriate clinical perspective.
POST-OPERATIVE CONSIDERATIONS AND THE INITIAL ENTERAL DIET Post-operative complications are common in patients following massive intestinal resection; re-exploration and further resection of necrotic bowel are frequently necessary, and the presence of intra-abdominal abscesses and fistula are common. The surgical team, often working in co-operation with the invasive radiology service, can usually resolve these immediate post-operative problems. If the patient has bowel, which has not been placed in continuity of the nutrient stream, an additional operation should be performed in a stabilized patient free of complications. Patients following massive intestinal resection are frequently quite ill in the perioperative period, and caregivers are often hesitant to subject a recuperating individual to subsequent operative procedures. Often, home discharge is one technique utilized to relieve the surgeon of the anxiety associated with the care of a patient who has sustained a catastrophic illness. However, if the patient is to progress through a programme of rehabilitation, then closing ostomies and placing all remaining bowel in continuity is a key undertaking to initiate this process. This important step early in the initial or a subsequent early hospitalization is necessary in order to maximize exposure of all of the available intestinal surface area to enteral nutrients and thereby enhance intestinal adaptation and maximize absorption.1,2 Enteral nutrient exposure is necessary to stimulate bowel adaptation, and attention should be specifically directed toward optimizing enteral feedings. Again, it should be emphasized that an additional operation should be undertaken only in a patient who has recovered from the initial resection and the risk of the procedure is low. If the initial surgical team is reluctant to operate on the patient, then a referral to a centre which specializes in complex gastrointestinal surgery is appropriate. Oral food intake is initiated as soon as the patient accepts meals and feeding is not contraindicated by the patient’s medical condition. Tube feedings are rarely used; rather, small hourly feedings of no more than 600 kcal/day given along with 30 ml of fluid/hour are provided. Foods high in complex carbohydrate, low in fat and high in protein are initially selected and rice, baked potatoes, and pasta served with chicken,
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fish or lean meat are the mainstay of this initial diet. Simple sugars should be avoided because of their osmotic contribution, which augments intestinal transit and diarrhoea. The goal of this approach is to control dietary intake and thereby prevent or control diarrhoea. Anti-motility agents should be initiated and, on occasion, anti-nausea medication is utilized. It usually takes weeks and, on occasion, months, for patients with SBS to tolerate this diet, but with bowel adaptation there is passage of semiformed stools indicating that the quantity of the diet can be gradually increased over time. In patients with ostomies, adaptation is characterized by a gradual decrease in the volume of the effluent. Practice points † all bowel should be placed in continuity before intestinal rehabilitation is started † the initial oral diet and fluid intake should be small, frequent feedings containing high complex carbohydrate and low-fat to prevent initial episodes of diarrhoea
SELECTION OF THE FINAL ENTERAL DIET The final enteral diet should be based on the anatomy of the retained bowel the presence or absence of a colon and the ileum. The ileum is important because it is a major site for the absorption of fat and fat-soluble vitamins, including vitamins A and D. In addition, the ileum is relatively efficient in water absorption. Consequently, resections involving only jejunum often result in little diarrhoea, and the concerns of malabsorption of fat and fat-soluble vitamins are not as great as if a comparable resection was performed removing the ileum. In addition to the colon’s importance in absorbing water and electrolytes, the large intestine plays a unique role in the patient with short bowel for it serves as a fermentation chamber where bacteria metabolize unabsorbed carbohydrate and, to lesser extent, protein. 3 The byproducts of this process (short-chain fatty acids) serve as fuels for the colon and other more distant tissue. While discussed in more detail elsewhere (see pages XXX), patients with a portion of colon in continuity should receive a high-carbohydrate, low-fat diet, while those with small bowel ostomies may take a diet containing more fat (Table 1). Because malabsorption exists in all individuals, the patients must become hyperphagic and consume 25 – 75% more macronutrients than usually required if enteral autonomy is to be expected. This goal is usually easily achieved in previously overweight individuals who enjoy eating, but patience and constant coaching are required in slender, fastidious individuals who have a habitually limited food intake.
Practice points † a six-feeding diet high in complex carbohydrate and low in fat should be provided to patients with a portion of colon in continuity † a more balanced diet can be provided to patients with ostomies
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Table 1. Suggested diets for patients with the short-bowel syndrome.
Carbohydrate (% of diet) Composition
Fat (%) Protein (%) Fibre Oxalates Fluid
Patients with colon
Patients without colon
60
50–55
Complex carbohydrate, no or minimal simple sugars 20 –25 15 –20 Provided as food fibre Low* To insure a urinary output of .1200 ml/day
25–30 15–25 Fibre minimized No special requirement May require isotonic fluids with salt added to accommodate ostomy losses
PARENTERAL NUTRITION—WHEN TO START AND WHEN TO STOP Intravenous (IV) support is required during the post-operative period, and because enteral feedings are initially limited, parenteral nutrition (PN) is usually initiated. The initial formulation should contain enough volume to insure hydration and adequate electrolyte replacement. Some calories (including fat emulsions containing essential fatty acids), adequate protein, vitamins, and trace elements should all be administered. A hypocaloric diet is initially safe and effective for individuals who are overweight4; even in normal weight individuals, the calorie load can be calculated to supplement enteral intake. Such a parenteral formulation usually does not suppress appetite, and with time the IV nutrition can be cycled and administered at night and enteral feedings are provided during the day. In our practice, we have enhanced adaptation in many individuals over the immediate post-operative period by administering growth factors, and therefore, during this time we initially rely on PICC lines, placed in the patient’s arms and directed into the superior vena cava, as an early means of parenteral access. Placement of this line does not require an operation and it is frequently removed at the time of discharge if sufficient gut adaptation has taken place. If a more permanent central venous catheter is required for home PN, a central indwelling line is placed shortly before discharge. Dependence on parenteral support is usually related on the length of the residual bowel and the ability of the patient to take enteral feedings. Clinical experience teaches that patients with , 50 –70 cm jejuno-ileum anastomosed to a portion of colon or those with , 100 –140 cm small bowel and no colon (an ostomy) will require long-term parenteral therapy, possibly for life. 5,6 Thus, a central line for nutrient infusion may become a life-line for long-term survival of these individuals; attention must be directed to appropriate line care in order to minimize potential complications and to ensure IV access. In patients with slightly longer segments of small bowel, PN is a temporary means of support until adaptation has occurred and until enteral feedings are adequate
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Table 2. Estimated length of time required for parenteral nutrition depending on bowel anatomy. Presence (þ ) Length of small or absence (2) bowel (cm) of colon Time on PN 80 –150 50 –70 40 –70 ,60 10 –30
þ or 2 þ þ 2 þ or 2
1–6 months 1–6 months 6–12 months Permanent Permanent
and can sustain the individual (Table 2). 7 The time necessary for adaptation appears to be greatly reduced with the use of growth factors. By monitoring body weight, urine and stool output and concentrations of serum electrolytes and indices of renal function, gradual weaning from PN is possible with time.
Practice points † parenteral support is usually required following an operation, and IV support can gradually be converted to include the provision of all essential nutrients administered by vein † PN should serve as a supplement to enteral feedings, not become the principal means to sustain nutrient intake † central venous access is life-saving in some individuals, and care should be taken to prevent central venous thrombosis and catheter infection † many patients can be weaned from parenteral support with time, and predictions of the duration of IV support can be made in the adult based on small bowel length. Alternatively, the use of growth factors appears to accelerate this process
BOWEL REHABILITATION—WHO WILL BENEFIT? Bowel rehabilitation is an approach to patients with SBS which emphasizes an appropriate diet and usually utilizes specific nutrients and growth factors to enhance intestinal absorption. Over the past 20 years, factors, which regulate intestinal mucosal cell turnover, have been extensively studied. Growth factors such as growth hormone (GH), insulin-like growth factor-1, epidermal growth factor and glucagon-like peptide-2 (GLP-2) are a few of the many important regulators controlling gut growth, but other factors such as the amino acid glutamine (Gln), specific fatty acids, bile salts, interleukin 11 and other substances are also important. 8 With the biosynthesis of GH and its availability in the 1980s, we initiated a programme to study the impact of available trophic factors on intestinal absorption in patients with SBS. Encouraged by findings in animal investigations9,10 and preliminary patient studies11, we initiated a phase I study to determine the safety and efficacy of this
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approach. These results suggested that about 40% of the PN-dependent patients studied were able to be weaned from IV feedings and remain independent of IV support during the 3– 5 years of follow-up. 12 In a prospective randomized double-blind multicentre phase III clinical trial, we evaluated the safety and efficacy of GH and Gln, given alone or in combination to 41 PN-dependent patients. 13 Eligible patients met the following conditions: male or female between 18 and 75 years of age; body mass index (BMI) . 17; small intestinal length , 200 cm (as determined from the operative report); the ability to ingest solid food, but requiring . 3000 PN calories/week; have acceptable liver and kidney function (a serum bilirubin level less than three times normal and a serum creatinine , 3 mg/dl) and have normal or compensated and stable hypertension and/or cardiovascular disease. The patients had to have undergone bowel resection at least 6 months prior to the study, have an intact stomach and duodenum and have , 3 l stool output/day. In addition, one of the following criteria was required: (1) . 30% of colon anastomosed to . 15 cm jejunumileum or (2) , 30% colon anastomosed to $ 90 cm jejunum-ileum. Exclusion criteria included a BMI . 28; pregnancy or lactation; a history of cancer within 5 years; chronic infection; neurological disorder, mental debility or a history of psychiatric eating disorder or drug of alcohol abuse; sustained hypertension ($ 160/100 mm Hg); secretory bowel disease (a stool output . 800 ml/day with no oral intake); diabetes mellitus; hypoxaemic pulmonary disease (resting pAO2 # 75 Torr); unstable ischaemic heart disease or uncompensated cardiac failure; ingestion of glucocorticoids $ 10 prednisone or equivalent; the use of immunosuppresant therapy; a history of carpal tunnel syndrome; the use of other investigational drugs # 30 days before study entry and the previous administration of GH or other growth factors to enhance intestinal absorption. Those subjects who met these criteria and were interested in the study underwent a complete history and physical examination and appropriate blood testing. The operative report of the previous resection was obtained and the history of body weight over the past 2 months was reviewed. Forty-one patients were eligible for study and all became study participants. The study was a randomized, double-blind, controlled, parallel-group multicentred phase III clinical trial. All participants were admitted to an assisted living facility for 6 weeks and were monitored by physicians, nurses, and dieticians. The initial 2 weeks was a baseline period, which allowed observation, stabilization, and initiation of optimal nutritional support (both oral diet and parenteral support). The subjects received an individualized enteral diet low in fat (20 –30%) and high in complex carbohydrate (60%) adjusted to the subject’s requirements. The meals were provided as six feedings throughout the day. The ingestion of simple sugars was discouraged. During the first week 3-day meal plans were designed and provided on a rotational basis throughout the study. A minimal level of oral fluid intake was determined and fluid ingestion was also encouraged and recorded throughout the study. At the end of this 2-week period, the nutritional therapy was continued and the subjects were randomized to receive one of three types of therapy: 1. oral Gln (30 g/day in divided doses) plus subcutaneous GH placebo injections; 2. oral Gln placebo (30 g/day in divided doses) plus subcutaneous GH (0.1 mg/kg); 3. oral Gln plus subcutaneous GH at the doses outlined above. The first group, which represented the effects of optimal dietary intake, served as a control group for the GH-alone and co-therapy groups. The random allocation to
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the groups was in the ratio of 1:2:2, thus resulting in a final sample size of nine in the control group, 16 in the GH group and 16 in the GH-plus-Gln group. During the next 4 weeks, the assigned treatment was provided daily and the patients were monitored by recording daily body weight, vital signs, symptoms and complaints. Oral intake and volume of urine and stool were also measured. Based on an algorithm that utilized this data, IV feedings were adjusted to accommodate for enteral absorption. After the conclusion of the 4-week inpatient study period, the patients were discharged on the enteral and parenteral diets that they received on the last week on therapy. The patients were followed as outpatients for the next 3 months. The GH was not administered during this time, but the Gln or Gln placebo was taken daily. A followup visit was performed on the last week of the 18-week study, and the final physical examination, body weight, nutritional history and blood studies were obtained at this time. The primary study endpoint was the change in weekly PN volume measured on week 2 (the second week of the baseline period) and compared with week 6 (the last week of the treatment period). Secondary end points included the change in weekly caloric content and frequency of PN administration/week. After 4 weeks of therapy, the reduction in PN volume and calories was determined as well of the frequency of PN infusion (Table 3). All subjects demonstrated a reduction in PN support, with the combination of GH and oral Gln treatment resulting in a greater reduction in PN volume, calories, and frequency when compared with GH or Gln given alone. Upon discharge there was some need to increase PN administration in selected patients but the response pattern remained the same as the initial response at the 18-week follow-up period. Smaller studies in patients with SBS have administered GLP-2 and reported enhancement in body composition related to this agent.14 The specific use of this growth factor in the rehabilitation of PN-dependent patients has not as yet been reported. How are patients selected who may have the best chance of responding to specific growth factor rehabilitative therapy? To address this issue, we prospectively studied 49 stable PN-dependent adult patients with short bowel.15 Patients with secretory diarrhoea (. 800 ml stool or ostomy loss while taking nothing by mouth over a 24 hour period) and those who had a history of cancer within 5 years of admission were
Table 3. Data from the randomized, multicentre, double-blind trial (13) showing the decrease in weekly PN requirements (mean þ SD).
Group Diet þ Gln Diet þ GH Diet þ GH þ Gln a b
n¼9 n ¼ 16 n ¼ 16
PN volume (l)
PN calories (kcal)
PN frequency (infusions/week)
3.8 ^ 2.4 5.7 ^ 4.0a 7.7 ^ 3.3b
2633 ^ 1341 4308 ^ 1870a 5751 ^ 2082b
2.0 ^ 0.9 3.0 ^ 1.8a 4.2 ^ 1.4b
GH ¼ growth hormone; Gln ¼ Glutamine. P , 0:05: P , 0:001; when compared with Diet þ Gln group.
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Table 4. The effect of growth hormone, glutamine and diet on outcome.
Length of small bowel (cm) Number Bowel length (cm) Off PN [# (%)] Reduced PN No change
Patients with a portion of colon
Patients with no colon
.70 8 122 5 (63) 3 (38)c 0
12 99 4 (33)b 6 (50) 2 (17)
,70 29 28 11 (38)a 16 (55) 2 (7)
a
Seven of these patients has ,35 cm of jejunum-ileum. All of these patients had .100 cm of jejunum-ileum. c Two of these patients had Crohn’s disease and the third had radiation enteritis. b
excluded from the study. All subjects underwent a month of inpatient therapy during which they were monitored and received an optimal diet, and GH and glutamine, as previously described. 11 The ability to remove patients from PN was related to bowel anatomy and, to a lesser degree, their primary diagnosis (Table 4). In patients with a portion of colon in continuity, about two-thirds of those with jejunoileal segments . 70 cm could be weaned from PN. As length of the residual small bowel diminished so did the success of this therapy. In the patients with , 70 cm of small bowel and colon, 38% of individuals were removed from PN. It is notable that seven of these individuals had , 35 cm of the jejunoileal segment remaining. Patients who most frequently failed to respond to this therapy had mucosal disease—Crohn’s disease or radiation enteritis—as the cause of their bowel resections. Four of the 12 patients with no colon became free from PN, but it is notable that all of these individuals had . 100 cm of remnant small bowel. Patients with shorter segments and ostomies remained PN-dependent, even thought the IV volume could be reduced in about 50% of these individuals. Thus, in patients with a portion of colon, the response to this form of intestinal rehabilitation is variable depending on small bowel length (Figure 1). However, many patients adapt following this form of therapy—we care for about a dozen patients with , 15 cm of jejuno-ileum anastomosed to colon who have been free of PN for years. Two of the women in this group have conceived, carried their babies to term and had normal deliveries. Other patients are able to reduce PN requirements, which enhances the individual’s quality of life. 16 Thus, in the group of patients with a portion of colon in continuity, a rehabilitation programme should generally be considered before contemplating a referral of the patient for intestinal transplantation. This is particularly true as new additional therapies that enhance bowel adaptation become available. In contrast, patients with very short segments of small bowel (, 50 cm) who have no colon have very large fluid losses which require parenteral replacement therapy. 17 The possibility of intestinal transplantation should be considered in these individuals, for no rehabilitation programme available at this time can wean such patients from parenteral therapy.
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Body Weight (kg)
90
Low probability 50% of adaptation probability
High probability of being free of TPN after treatment with GH, GLN + diet
80
High probability of adaptation with short term TPN
70 60 50 40 30
0
20
40
60
80
100
Jejunal-ileal Length (cm) Figure 1. This chart uses probabilities to predict the success of weaning from parenteral nutrition, a patient with the short-bowel syndrome and a portion of the colon in continuity. To determine the outcome for an individual patient, locate the point at which bowel length and body weight cross. The area identified will describe the predicted outcome. Reproduced from Wilmore DW and Byrne TA. Approach to the patient with short-bowel syndrome. In Wolfe MM (ed). Therapy of Digestive Disorders, p 563. Philadelphia: Saunders, 1999.
Practice points † bowel rehabilitation which enhances intestinal adaptation is possible in patients utilizing an optimal diet, glutamine and GH † approximately 40% of PN-dependent patients become free of IV support over the long-term following such a programme † patients with a portion of colon represent appropriate candidates for such therapy. Small bowel length is the next predictor of success † in patients with no colon and small bowel ostomies and short intestinal segments (, 50 cm) intestinal transplantation at this time should be considered as the only therapy available to remove such individuals from PN
INDICATIONS FOR INTESTINAL TRANSPLANTATION Transplantation of the intestinal tract, with or without other visceral organs, has become more popular in recent years, given the poor outlook for PN-dependent patients with SBS.18 The international intestinal transplant registry reported the results from 273 transplants in 260 patients who received intestinal grafts19; 59% of the group received multiorgan grafts. In addition to a segment of small bowel, a liver was transplanted to replace the organ that was irreversibly damaged because of PN and other conditions associated with short bowel. Isolated small-bowel transplants, with or without colon, were reported in 41% of recipients; 1 year actuarial patient survival was 69% and graft survival was 55%. Thus, this procedure should not be viewed as a low-risk approach. In addition to the patients with end-stage liver disease, there may be other indications (relative or absolute) to consider in exploring this treatment option with
904 D. W. Wilmore
a patient. This is particularly true in individuals who do not have IV access (a rarity), or those who have life-threatening complications associated with PN (severe liver dysfunction, recurrent sepsis including fungaemia, etc.). Those patients with extremely short segments of jejunum-ileum and no colon have to this point in time not been able to be weaned from PN with current rehabilitation programmes, and intestinal transplantation should be discussed with these individuals as a treatment option.
Research agenda † intestinal transplantation is evolving, and this possibility should be explored with those eligible patients with no colon and short segments of small bowel (, 50 cm) † other patient groups to be considered are those who fail rehabilitation programmes and have life-threatening complications associated with PN, or those with irreversible liver disease † much research remains to be performed in this field. Research animals (particularly rodents) have been used as models for this syndrome, but their adaptive response is characterized by mucosal hypertrophy, which has not been observed in the human condition.20,21 This emphasizes the need for patient studies that require multicentre trials. Such investigations should be based in centres with interest and expertise in intestinal failure, and there are now in the USA about six of these centres of excellence. Such studies should include the evaluation of additional growth factors, given individually and in combination, to enhance bowel adaptation. The mechanisms by which Gln (and other nutrients) augment these responses need to be explored. Re-treatment or periodic treatment with growth factors may be necessary in some individuals, and this effect along with the dosage used and frequency of treatment should be studied. Small bowel segments are usually transplanted without colonic segments, and protocols need to be established which allow safe transplantation of large bowel, in order to evaluate its effect on residual function of the small intestine † while animal studies may be helpful, studies should be performed in humans with this condition † combinations of growth factors and nutrients should be tested in humans to determine the optimal therapy to enhance intestinal adaptation † studies should be performed transplanting colon along with small bowel in order to determine the role of the large bowel in intestinal function
SUMMARY The SBS occurs following massive intestinal resection and is a devastating event for patients. Diarrhoea, malabsorption, and malnutrition are the major symptoms. However, by initially supporting the patient with parenteral feedings and providing appropriate enteral feedings and gradually increasing oral intake, adaptation of the intestinal tract occurs. This response is characterized by an increase in intestinal absorption. Depending on the length of the residual bowel, the patient may become independent of parenteral nutritional support. This process is enhanced in selective
Specific therapy in rehabilitation 905
BOWEL REHABILITATION
FOLLOW UP
SHORT TERM TPN
LONG TERM TPN
BOWEL RESECTION
BOWEL TRANSPLANTATION Figure 2. A general care map that can be utilized in the treatment of patients with the short-bowel syndrome. The initiation of bowel rehabilitation in the immediate post-operative period has greatly shortened nutritional support and at times eliminated the need for long-term home parenteral nutrition. Reprinted with permission from the American Society for Parenteral and Enteral Nutrition (ASPEN.) from the following: Wilmore DW. Growth factors and nutrients in the short-bowel syndrome. Journal of Parenteral and Enteral Nutrition (JPEN) 1999;23:S119, Figure 1. ASPEN does not endorse the use of this material in any other form than its entirety.
individuals with an appropriate diet and the administration of GH and glutamine (Figure 2). Other growth factors will undoubtedly be successfully used in this process as more clinical data become available. However, some patients with very short segments of jejuno-ileum and no colon have such large fluid and electrolyte losses that small-bowel transplantation may be the only therapeutic approach to achieve enteral independence and reverse intestinal failure in these individuals.
REFERENCES 1. Levin GM, Daren JJ, Steiger E et al. Role of oral intake in maintenance of gut mass and disaccharidase activity. Gastroenterology 1974; 67: 975–982. 2. Feldman EJ, Dowling RH, McNaughton J et al. Effect of oral versus intravenous nutrition on intestinal adaptation after small bowel resection in the dog. Gastroenterology 1976; 70: 712–719. 3. Nordgaard I, Hansen BS & Mortensen PB. Colon as a digestive organ in patients with short bowel. Lancet 1994; 343: 373–376. 4. Dickerson RN, Posato EF & Mullen JL. Net protein anabolism with hypocaloric parenteral nutrition in obese stressed patients. American Journal of Clinical Nutrition 1986; 44: 747–755. 5. Dudrick SJ, Latifi R & Fosnocht DE. Management of the short bowel syndrome. Surgery Clinics of North America 1991; 71: 625–643. 6. Rombeau JL & Rolandelli RH. Enteral and parenteral nutrition in patients with enteric fistulas and short bowel syndrome. Surgery Clinics of North America 1987; 67: 551–571. * 7. Gouttebel MC, Saint-Aubert B, Astre C & Joyeux H. Total parenteral nutrition needs in different types of short bowel syndrome. Digestive Diseases and Sciences 1986; 31: 718 –723. 8. Drucker DJ. Epithelial cell growth and differentiation. I. Intestinal growth factors. American Journal of Physiology 1997; 273: G3–G6. * 9. O’Dwyer ST, Smith RJ, Hwang TL & Wilmore DW. Maintenance of small bowel mucosa with glutamineenriched parenteral nutrition. Journal of Parenteral and Enteral Nutrition 1989; 13: 579–585. * 10. Ulshen MH, Dowling RH, Fuller CR et al. Enhanced growth of small bowel in transgenic mice over expressing bovine growth hormone. Gastroenterology 1993; 104: 1205– 1208. * 11. Byrne TA, Persinger RL, Young LS et al. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Annals of Surgery 1995; 222: 243–254. * 12. Wilmore DW, Lacey JM, Soultanakis RP et al. Factors predicting a successful outcome after pharmacologic bowel compensation. Annals of Surgery 1997; 226: 288–292.
906 D. W. Wilmore * 13. Byrne TA, Lautz D, Iyer K et al. Recombinant human growth hormone (rhGH) reduces parenteral nutrition (PN) requirements in patients with the short bowel syndrome: a prospective, randomized, double-blind, placebo-controlled study. Journal of Parenteral and Enteral Nutrition 2003; . in press. 14. Jeppesen PB, Hartmann B, Thulesen J et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology 2001; 120: 806 –815. * 15. Byrne TA, Nompleggi DJ & Wilmore DW. Advances in the management of patients with intestinal failure. Transplantation Proceedings 1996; 28: 2683– 2690. 16. Rovera GM, Anderson S, Camelio M et al. Enhancing outcome in patients receiving long term tpn. Clinical Nutrition 2000; 19: 2. 17. Nordgaard I, Hansen BS & Mortensen PB. Importance of colon support for energy absorption as smallbowel failure proceeds. American Journal of Clinical Nutrition 1996; 64: 222– 231. 18. Van Gossum A, Vahedi K, Abdel-Malik et al. Clinical, social and rehabilitation status of long-term home parenteral nutrition patients: results of a European multicenter survey. Clinical Nutrition 2001; 20: 205–210. 19. Grant D. Intestinal transplantation: 1997. Report of the International Registry. Intestinal Transplant Registry. Transplantation 1999; 67: 1061–1064. 20. Porus RL. Epithelial hyperplasia following massive small bowel resection in man. Gastroenterology 1965; 48: 753–757. 21. O’Keefe SJD, Haymond MW, Bennett WM et al. Long-acting somatostatin analogue therapy and protein metabolism in patients with jejunostomies. Gastroenterology 1994; 107: 379 –388.