Review

Nutrition and management of enterocutaneous stula

D. A. J. Lloyd1 , S. M. Gabe1,2 and A. C. J. Windsor3
1 The Lennard-Jones Intestinal Failure Unit, St Marks Hospital and Academic Institute, Harrow, 2 Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Imperial College, London and 3 Department of Surgery, University College Hospital, London, UK Correspondence to: Dr D. A. J. Lloyd, The Lennard-Jones Intestinal Failure Unit, St Marks Hospital and Academic Institute, Watford Road, Harrow HA1 3UJ, UK (e-mail: dajl@btinternet.com)

Background: The management of enterocutaneous stula is challenging, with signicant associated

morbidity and mortality. This article reviews treatment, with emphasis on the provision and optimal route of nutritional support. Methods: Relevant articles were identied using Medline searches. Secondary articles were identied from the reference lists of key papers. Results and conclusion: Management of enterocutaneous stula should initially concentrate on correction of uid and electrolyte imbalances, drainage of collections, treatment of sepsis and control of stula output. The routine use of somatostatin infusion and somatostatin analogues remains controversial; although there are data suggesting reduced time to stula closure, there is little evidence of increased probability of spontaneous closure. Malnutrition is common and adequate nutritional provision is essential, enteral where possible, although supplemental parenteral nutrition is often required for high-output small bowel stulas. The role of immunonutrition is unknown. Surgical repair should be attempted when spontaneous stula closure does not occur, but it should be delayed for at least 3 months.
Paper accepted 7 June 2006 Published online 27 June 2006 in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.5396

Introduction

Enterocutaneous stulas are abnormal communications between the gastrointestinal tract and the skin. Although rare, they are associated with considerable morbidity and mortality. Death related to enterocutaneous stula remains disproportionately high compared with that associated with other surgical conditions. Studies reported over the past 30 years have shown mortality rates of 541 per cent1 25 , with rates of 633 per cent in the most recent case series4,13,15,17 . Sepsis was the leading cause of death in all of these studies. Increased mortality has been shown to be associated with high initial stula output and the presence of complications4 ; logistic regression analysis by Altomare et al.26 identied increased Acute Physiology And Chronic Health Evaluation II scores and low serum albumin concentrations as predictors of mortality. Similar multivariable logistic regression analyses of retrospective data from St Marks Hospital identied high initial stula output and the presence of patient co-morbidity as factors increasing the risk of death (unpublished observations).
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The management of enterocutaneous stula continues to present a considerable challenge to surgeons, gastroenterologists and allied professionals, and this has resulted in a variety of different management strategies. Patients have frequently undergone several operative procedures, and their physiological and nutritional reserves are often severely compromised. Management should focus initially on correction of uid and electrolyte disturbances, aggressive treatment of sepsis and control of stula output. Nutritional requirements must be addressed and attention paid to skin care and psychological support. Only after these issues have been dealt with adequately, and if the stula persists after conservative measures, should further surgery be contemplated. This article reviews the management of stulas arising from the small intestine and colon, with particular emphasis on the provision and optimal route of nutritional support. Where possible, the article explores the evidence basis behind management protocols. However, much of the literature concerning enterocutaneous stula is in the form of retrospective reviews, usually originating from large
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specialist centres with expertise in the management of such conditions. There are few large randomized controlled trials addressing optimal management, and none has investigated the optimal routes of nutrition.
Fistula formation and characterization

predict stula closure, both spontaneous and operative, and death.

Spontaneous closure
Rates of spontaneous stula closure range from 19 per cent18 to 92 per cent12 , although the upper extremes reect small studies with selected subgroups of patients. Even in larger patient groups considerable variation exists, as demonstrated in data from four large patient populations published in recent years. Campos et al.4 reported a spontaneous closure rate of 31 per cent in a group of 188 consecutive patients with enterocutaneous stulas treated in Brazil over a 10-year period. This group included patients with pancreatobiliary stulas, which traditionally are thought to have a higher rate of spontaneous closure; the spontaneous closure rate dropped to 26 per cent once these patients had been excluded. Li et al.17 reported a spontaneous closure rate of 37 per cent in a review of 1168 patients treated over a 30-year period. Hollington et al.15 described ndings over an 11-year period at St Marks Hospital, with a spontaneous closure rate of 20 per cent in 277 patients treated between 1992 and 2002. However, Haffejee13 reported a much higher spontaneous closure rate of 75 per cent in 147 patients treated in Durban between 1990 and 1999. The range of spontaneous closure rates in these studies suggests differences in patient populations and enterocutaneous stula characteristics. Factors believed to predict spontaneous stula closure are shown in Table 1. Multivariable analysis by Campos et al.4 of the data from Brazil indicated that spontaneous closure was signicantly more likely with low-output stulas (odds ratio (OR) 298 (95 per cent condence interval (c.i.) 110 to 810)), but signicantly less likely when the stula had a non-surgical aetiology (OR 020 (95 per cent c.i. 005 to 081)), and when there were infective or non-infective complications (OR 006 (95 per cent c.i. 002 to 024) and 008 (001 to 070) respectively).

It is estimated that 7585 per cent of enterocutaneous stulas form after operation as a result of bowel injury, inadvertent enterotomy and/or anastomotic leakage27 ; the incidence of enterocutaneous stula formation may, therefore, be inuenced by the skill and experience of the surgeon as well as by patient variables28 . Fistula formation is more commonly associated with surgery in the presence of malignancy or inammatory bowel disease, and with attempted division of dense adhesions27 . In the remaining 1525 per cent of instances, enterocutaneous stulas form spontaneously secondary to underlying pathology. Inammatory bowel disease, in particular Crohns disease, is the commonest cause of spontaneous enterocutaneous stulation in the developed world27 ; other causes include radiation enteritis, diverticular disease, malignancy, intra-abdominal sepsis and trauma10,27,29,30 . In developing countries, spontaneous stulation may complicate infectious conditions, such as abdominal tuberculosis, amoebiasis and typhoid13 . There is no universally accepted classication scheme for enterocutaneous stulas. Characterization is usually made on the basis of anatomy (site of origin, simple or complex stula, end or lateral stula, and presence or absence of distal obstruction) or stula output (with high output usually dened as more than 500 ml per 24 h). The exact anatomy of an enterocutaneous stula is usually delineated by a combination of clinical observation, biochemical analysis of stula efuent and radiological investigation, of which contrast studies, such as computed tomography (CT) and magnetic resonance imaging, are the most commonly employed. Thorough initial characterization of an enterocutaneous stula is important as it provides prognostic information, which, in turn, may inuence the choice of treatment.
Fistula closure

Table 1

Factors that predict spontaneous stula closure4,40

The goal is stula closure with minimal morbidity and mortality. Many retrospective studies have reported experience from around the world1,4 6,8,10,12,13,15 20,22 25,27,29,31 39 . Comparison between these studies is difcult because of the different caseloads in various centres and differences in management protocols. However, they emphasize a high associated mortality and give some insight into factors that
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Surgical aetiology Free distal ow Healthy surrounding bowel Simple stula with no associated abscess cavity Fistula tract > 2 cm Fistula tract not epithelialized Enteral defect < 1 cm (with no discontinuity) Low stula output No co-morbidity

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Surgical closure
Although many enterocutaneous stulas close spontaneously, if the stula remains open after 2 months surgical intervention is likely to be needed as spontaneous closure is unlikely after this interval20 . The timing of corrective surgery in relation to the initial operation(s) is important, as it affects the incidence of further complications35 . Major abdominal surgery stimulates the formation of dense adhesions, especially when complicated by intraabdominal sepsis. This reaction is most severe between 3 weeks and 3 months after operation, and further surgery during this time is more likely to be complicated by stula recurrence35,41 . Delayed surgery also allows time for metabolic and nutritional deciencies to be corrected. Recent retrospective reviews have described overall rates of successful enterocutaneous stula closure (spontaneous combined with surgical closure) ranging from 69 to 93 per cent4,15,17,35 . In the report by Campos et al.4 , multivariable analysis indicated that successful surgical closure was associated only with the absence of complications (OR 020 (95 per cent c.i. 009 to 045) for infective complications and 024 (007 to 080) for non-infective complications); interestingly, nutritional support-related complications did not have a signicant effect on closure. Lynch et al.35 reported that surgical technique was a predictor of stula recurrence after surgery, with a 33 per cent incidence of recurrence after wedge repair or oversewing, compared with 18 per cent after resection of the stula; this was even more pronounced in patients with Crohns disease (75 versus 15 per cent). Multivariable analysis of data from St Marks Hospital indicates that successful closure is associated with low initial stula output and an absence of co-morbidity (unpublished observations).
Management principles

the stula efuent or to complications of treatment, such as central venous catheter infection, and it should be treated with appropriate antibiotics, guided by culture sensitivity. In addition, intra-abdominal collections should be drained promptly. Although, in the past, this may have meant further surgery, today most collections can be drained externally under ultrasonographic or CT guidance. The enzyme content of stula efuent, coupled with prolonged exposure of the peristula skin to moisture, can lead to rapid tissue breakdown around a stula. This prevents spontaneous closure and predisposes to infection. It is also painful and distressing to the patient. Effective skin care can be achieved with a combination of appliances and barrier products; in the hands of an experienced practitioner the results can be dramatic (Fig. 1). In addition, the collection of stula efuent allows output to be measured accurately, thereby assisting uid and electrolyte replacement. Psychological support is sometimes overlooked, but is of great importance. Patients with enterocutaneous stula have usually undergone major surgery and suffered a signicant complication. They also face the prospect of a prolonged hospital stay. In addition, the combination of an open wound and the production of stula efuent is likely to have a detrimental effect on body image. All of these features lead to psychological distress that must be addressed adequately.
Control of stula output

The initial imperative is stabilization of the patient. This should occur either before or in parallel with the investigation and characterization of the stula. Stabilization should focus on correction of uid depletion and any electrolyte imbalance. With high-output enterocutaneous stulas dehydration and hyponatraemia are common. There may also be signicant loss of potassium, chloride and bicarbonate ions, depending on the exact site of origin of the stula, and the content of the efuent must be accounted for when calculating electrolyte replacement40,42 . Blood transfusion may be required if there is signicant anaemia. Sepsis is common in patients with enterocutaneous stula23,43 , and rapid and aggressive treatment is required as sepsis is the commonest cause of death4,15,20 . Infection may be due to ongoing anastomotic leakage, to effects of
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Manipulation of stula output is important. Minimization of uid and electrolyte uxes aids in the management of accurate uid and electrolyte balance, and may allow a patient to be weaned off parenteral nutrition and uid support. In addition, reduction in the volume of irritant efuent facilitates skin care. However, it is debatable whether or not reducing output promotes spontaneous stula closure. Although there is evidence that low-output stulas have a greater rate of spontaneous closure than high-output stulas4 , the evidence that reducing output increases the likelihood of spontaneous closure is less convincing. This is discussed in more detail below in the setting of somatostatin and octreotide administration. The basic principles behind the reduction of stula output are similar to those used in the management of short bowel syndrome, and are summarized in Table 2. Intake of uids low in sodium should be restricted and electrolyte solution containing high concentrations of both sodium and glucose substituted. Gastric secretions can be reduced using H2 receptor antagonists or proton pump inhibitors, and bowel transit can be slowed with high
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Table 2

Methods of reducing stula output

Restrict hypo-osmolar uids Encourage electrolyte mix Antisecretory agents Protein pump inhibitors Somatostatin or octreotide Antimotility agents Loperamide Codeine

doses of antimotility agents, such as codeine phosphate or loperamide44 .

Dressed wound

Somatostatin and analogues

Somatostatin is a naturally occurring peptide hormone that has an inhibitory effect on gastrointestinal secretion45 . Its plasma half-life is 12 min and so it must be administered by continuous intravenous infusion. It reduces the secretion of a range of gastrointestinal hormones, including gastrin and cholecystokinin, which in turn reduce gastric and pancreatic secretions. In addition, somatostatin reduces splanchnic blood ow, reduces the rate of gastric emptying and inhibits gallbladder contraction. Because of its short half-life, a number of synthetic analogues have been developed, and of these octreotide is used most commonly in the treatment of gastrointestinal stula13,46 60 . Its signicantly longer half-life61 allows it to be given by intermittent subcutaneous injection (usually three times daily) but, although similar, the receptor binding properties of somatostatin and octreotide are not identical and, as a result, their actions may not be equivalent62 . A single small randomized controlled trial has compared somatostatin and octreotide in the management of gastrointestinal stula and suggests that octreotide may be less effective at promoting stula closure55 . Data from clinical trials investigating the benet of somatostatin and octreotide in the management of enterocutaneous stula have been reviewed recently62 . A number of randomized controlled trials and nonrandomized studies have been performed comparing supplemental somatostatin or octreotide with standard treatment alone13,39,46 50,52 54,56,57,60,63 72 . A summary of the randomized clinical trials of somatostatin and octreotide use is shown in Table 3. All of these studies are small, and differences in patient recruitment and study design make comparison and data pooling difcult. Only one study55 showed a signicant improvement in the spontaneous closure rate with somatostatin or octreotide. However, most trials showed a reduction in the time to stula closure51,69 72 , with the data
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Wound at 7 weeks

Fig. 1

Wound dressed with large Eakin appliance using seals and paste and appliance changed daily. Wound size reduced from a 24 29 cm to b 16 20 cm over a 7-week interval

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Table 3

Randomized clinical trials of octreotide and somatostatin use

No. of patients 25 20 20 10 19 17 15 40 45 16 17 14 17 11 8 Closure (%) 78 19 85 81 84 65 27 65 56 94 82 57 35 9 38 Time to closure (days) 13 19 14 20 N.A. N.A. N.A. 18 27 N.A. N.A. N.A. N.A. N.A. N.A. Mortality rate (%) N.A. N.A. N.A. N.A. N.A. N.A. N.A. 25 31 N.A. N.A. 14 12 N.A. N.A.

Reference Isenmann et al. Torres et al.71 Leandros et al.55

72

Treatment Somatostatin Control Somatostatin Control Somatostatin Octreotide Control Octreotide Control Octreotide Control Octreotide Control Octreotide Control

Comments 53% pancreatobiliary stulas. Closure assessed at day 14

Hernandez-Aranda et al.51 * Jamil et al.52 Sancho et al.58 Scott et al.59

Excluded cases unlikely to close spontaneously. Closure assessed at day 21 Closure assessed at day 20 Closure assessed at day 12

*Small bowel only. N.A. data not available. P < 0050 versus control.

favouring somatostatin over octreotide62 . Similarly, trials of somatostatin infusion tend to show a signicant reduction in stula output39,64,70,71 , whereas those for octreotide injection have more inconsistent results56,59,67 . In summary, it appears that somatostatin infusion, although possibly not octreotide injection, reduces stula output and decreases time to closure. However, there is little evidence to suggest that either agent increases the overall likelihood of spontaneous stula closure.
Nutritional support

Historical perspectives
Papers dating from before the widespread availability of parenteral nutrition highlight the potential for signicant malnutrition in patients with enterocutaneous stula. In a review of 157 patients treated at Massachusetts General Hospital between 1946 and 1959, the incidence of malnutrition ranged from 20 per cent in patients with a colonic stula to 74 per cent in those with jejunal or ileal stulas; the incidence of malnutrition in patients with gastric or duodenal stulas lay between these extremes at 53 per cent10 . The authors highlighted the relationship between incidence of malnutrition and mortality, with an overall mortality rate of 54 per cent for small intestinal stulas compared with 16 per cent for colonic stulas. This point was again highlighted in a smaller study published 4 years later, in which 56 patients with enterocutaneous stula were reviewed6 . The authors judged that 33 per cent had optimal nutritional support, dened as more than 3000 kcal/day and positive nitrogen balance via a combination of oral, tube and intravenous
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feeding. The stula closure rate was 89 per cent and the overall mortality rate 12 per cent in this group, compared with a closure rate of 37 per cent and overall mortality rate of 55 per cent in patients judged to have received suboptimal nutrition. In a follow-up to the earlier review from Massachusetts General Hospital, Soeters et al.23 compared mortality in patients with enterocutaneous stulas treated before and after the advent of parenteral nutrition. The overall mortality rate between 1970 and 1975, when hyperalimentation with parenteral nutrition was employed routinely in the treatment of patients with enterocutaneous stula, was 211 per cent, compared with a combined overall mortality rate of 44 per cent between 1946 and 1959. However, mortality between 1960 and 1970 was also low, with a combined mortality rate of 151 per cent. As parenteral nutrition was rarely used in the 1960s, other factors, such as improved monitoring, uid balance management and control of sepsis, as well as an increasing awareness of the importance of nutrition, may have been more important than the introduction of parenteral nutrition per se in reducing the number of deaths in these patients.

Malnutrition
There are multiple factors that contribute to malnutrition in patients with enterocutaneous stulas. The supply of nutrients may be limited, due to either anorexia or restriction of oral intake. Signicant loss of protein, electrolytes and uids can occur in stula efuent as a result of loss of small bowel secretions that would ordinarily be reabsorbed28 . Loss of ingested nutrients
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through high-output stulas originating from the small intestine effectively causes short bowel syndrome with resulting intestinal failure. Finally, patients often have increased energy demands as a result of ongoing sepsis and inammation, although this is countered to a degree by reduced demands resulting from immobility. Adequate nutrition inuences many aspects of care. It is widely accepted that malnutrition results in impaired wound healing and increases the risk of postoperative infection73,74 . Studies have shown a signicantly higher incidence of complications and higher mortality rates in malnourished patients undergoing abdominal surgery for both benign and malignant gastrointestinal disease75,76 . A retrospective review of 771 patients, both surgical and medical, from Pittsburgh revealed that evidence of malnutrition was associated with an almost threefold increase in minor complications, a threefold increase in major complications and a fourfold increase in mortality77 .

encountered in trauma patients fed parenterally is due to overfeeding83 . Finally, it is noteworthy that somatostatin and octreotide inhibit the secretion of both insulin and glucagon62 , and treatment with these agents may be associated with increased blood glucose concentrations. Theoretically, this may be detrimental in the acute setting, although this has not so far been demonstrated in practice.

Enteral versus parenteral feeding

There is ongoing discussion about which is the better route of nutrition, and linked to this is the debate about whether periods of bowel rest are benecial or detrimental in patients with stulas. After the introduction of parenteral feeding, the practice of total parenteral nutrition (TPN) for enterocutaneous stula was adopted widely. However, it should be remembered that the primary role of nutritional support, whether enteral or parenteral, is the prevention of malnutrition. Evidence of an additional therapeutic role for TPN in the promotion of stula healing is currently lacking, and parenteral nutrition carries with it the risks of central venous catheter sepsis, venous thrombosis and pneumothorax. The widespread availability of parenteral nutrition since the 1970s has doubtlessly helped to reduce the incidence of malnutrition in patients with high-output enterocutaneous stulas. It has also been suggested that this has inuenced stula closure rates and mortality positively84 , although this notion has not been borne out by some historical studies23 . The concept of bowel rest in this setting is based on the observation that gastrointestinal secretions drop by 3050 per cent in patients receiving TPN40 and that this might aid stula closure. However, although this may improve uid and electrolyte balance, published data to suggest an improvement in spontaneous stula closure do not exist, as randomized trials investigating outcomes in patients kept nil by mouth have not been performed. Interestingly, in the series of 1168 patients reported by Li et al.17 , only 136 per cent received parenteral nutrition exclusively yet mortality was very low and overall closure rates high. Drawing comparisons with data on the use of somatostatin and octreotide provides little evidence that reducing stula output increases the chance of spontaneous stula closure62 . In addition, some authors have reported that enteral elemental diets may reduce stula output as much as TPN9 , with similar rates of spontaneous stula closure and mortality20 . Levy et al.16 have reported their experience of managing enterocutaneous stulas in a national referral centre in Paris. They employed an aggressive approach to enteral feeding and, although many of their patients received
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Metabolism
No study has specically investigated metabolic derangement from enterocutaneous stula. However, although patients with an established stula may have minimal metabolic derangement, those who are critically ill or septic in the postoperative period will be metabolically compromised. Critical illness is associated with a catabolic state typied by hyperglycaemia, lipolysis and marked proteolysis. This proteolysis may result in signicant skeletal muscle loss, which cannot be prevented by nutrition alone. These catabolic effects are believed to be mediated by inammatory cytokines, such as tumour necrosis factor (TNF) 78 , although the process is complex and interventions to block a single component (for instance TNF-) have not been shown to affect the catabolic response signicantly79 . The hyperglycaemia seen in critical illness is associated with insulin resistance80 , and with release of glucagon and endogenous corticosteroids causing subsequent gluconeogenesis81 . There is increasing evidence that tight glycaemic control is important in the care of the critically ill. Van den Berghe et al.82 demonstrated a worthwhile reduction in mortality and morbidity in a large series of postoperative patients in an intensive care setting (63 per cent after cardiac surgery) in whom intensive insulin therapy was used to maintain blood glucose levels between 44 and 61 mmol/l. Although it is important to avoid underfeeding patients with an enterocutaneous stula, it is also necessary to understand that overfeeding may be deleterious. Because of the relative insulin resistance described above, overfeeding may result in worsening hyperglycaemia, hypertriglyceridaemia and hepatic steatosis, and it has been suggested that the increased sepsis
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parenteral nutrition for a short initial period, 85 per cent of the 335 patients so treated were switched to exclusive enteral nutrition. Spontaneous stula closure was achieved in 38 per cent of 234 patients managed conservatively, with a mortality rate of 19 per cent16 . These results are similar to those of other retrospective reviews in which a much higher proportion of patients were fed parenterally2,20,25 . A number of the patients described by Levy et al.16 received enteral nutrition via the stula, a technique known as stuloclysis that has recently been described in detail85 . Teubner et al.85 used stuloclysis in 12 patients with stula from the jejunum or ileum who were awaiting reconstructive surgery, and found it possible to discontinue parenteral nutrition in 11 of them. The patients received either polymeric, semielemental or elemental feeds, depending on tolerance. A similar technique is the reinfusion of uid from a proximal stula into a distal mucous stula, with or without additional nutritional supplementation. This has the potential advantage of preserving small bowel secretions, although it is unacceptable to many patients. Another technique that has been used to facilitate enteral feeding is vacuum sealing of the stula tract86 88 . This has been described in a series of 74 patients with postoperative enterocutaneous stula who were fed orally; a high rate of spontaneous stula closure was reported87 . There is a large body of evidence in the critical care literature that suggests enteral nutrition is superior to parenteral nutrition in intensive care and postoperative settings. Meta-analysis by Heyland et al.89 demonstrated a reduced incidence of infection in patients requiring intensive care who received enteral rather than parenteral nutrition, although overall mortality was not affected. Given the high mortality rate from sepsis in patients with stulas, this may be clinically relevant. It has been suggested that TPN induces small intestine mucosal atrophy, which, in turn, allows increased bacterial translocation across the gut mucosal barrier. However, although TPN induces marked mucosal atrophy in rodent models, its effect in humans is much less dramatic and the results of clinical studies are mixed90 92 . There is interest in the hormonal mechanisms that might mediate intestinal mucosal atrophy, with peptides implicated, including epidermal growth factor (EGF), somatostatin and glucagon-like peptide (GLP) 2. EGF reduces bacterial translocation in a rat model of TPN-induced mucosal atrophy93 . Somatostatin is believed to induce intestinal atrophy, which may be relevant if considering its use in patients with enterocutaneous stula, and somatostatin antagonists may provide some benet in an elemental diet-induced rat model of mucosal atrophy94 .
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GLP-2 is a gut peptide secreted in response to luminal nutrients that has a trophic effect on the bowel. Little is known about the effects of enteral and parenteral feeding on healing of the intestinal mucosal in those with enterocutaneous stula. Early enteral feeding after elective gastrointestinal surgery has been shown to be superior to nil by mouth regimens with regard to lower complication rates95 and reduced hospital stay. Meta-analysis suggested that early enteral feeding might reduce the risk of anastomotic dehiscence, although this was not statistically signicant. The concept that enteral feeding is not only safe but may improve anastomotic healing is supported by limited data from experimental models suggesting that enteral feeding increases anastomotic strength compared with parenteral feeding, possibly via trophic effects on the intestinal mucosa96 .

Immunonutrition
Over the past decade there has been increasing interest in the use of specially formulated feeds, both enteral and parenteral, to modulate the immune response to injury and illness. Although no study has specically examined the role of these feeds in patients with enterocutaneous stula, there is increasing evidence that they may be benecial in the management of malnourished surgical and critically unwell patients. This has led to the publication of guidelines on their use97 . A full discussion of the potential benets of immune-enhancing feeds is beyond the scope of this article, but the role of glutamine and the use of immune-enhancing enteral feeds are worthy of brief mention in the context of enterocutaneous stula management. Glutamine is considered to be a conditionally essential amino acid; although it is synthesized in most tissues, plasma concentrations become depleted when consumption is increased, such as in metabolic stress and infection98 . Glutamine acts as both a nitrogen and energy source for lymphocytes and small intestinal mucosa, and reduced concentrations are associated with immune dysfunction and poor outcomes99 . A meta-analysis of the use of this agent in critical care revealed a signicant reduction in infectious complications (relative risk (RR) 080 (95 per cent c.i. 064 to 100)), but no signicant effect on overall mortality100 . Subgroup analysis showed that elective surgical patients had a signicant reduction in the number of postoperative complications (RR 036 (95 per cent c.i. 014 to 092))100 . The effect of glutamine supplementation was noted with high-dose (more than 02 g per kg per day) parenteral glutamine supplementation100 ; data supporting enteral glutamine supplementation are less convincing101 . Several meta-analyses have investigated the potential benet of enteral feeds containing various combinations of
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arginine, omega-3 fatty acids, antioxidants and nucleotides in critically ill and postoperative patients102 104 . These all show reductions in the rate of infectious complications and length of hospital stay in those receiving enteral immunonutrition compared with standard enteral feeds102 104 . As with glutamine supplementation, there was no effect on overall mortality102 104 . Subgroup analysis in the largest of these meta-analyses again demonstrated a signicant benet in surgical patients (RR 053 (95 per cent c.i. 042 to 068)), but suggested that there might be increased mortality in the critically ill (RR 146 (95 per cent c.i. 101 to 211))104 . A further multicentre study demonstrated increased mortality in critically ill patients with severe sepsis receiving enteral immunonutrition compared with those fed parenterally, although data were analysed from only 39 patients105 . There is concern that immuneenhancing diets in the critical care situation may actually worsen the systemic immune response syndrome, and so the precise role of enteral immunonutrition in this setting remains controversial.
Conclusion

Treatment of enterocutaneous stula should concentrate initially on correction of uid and electrolyte imbalances, drainage of collections, treatment of sepsis and control of stula output. Malnutrition is common, and nutritional assessment and provision are essential. Although restriction of enteral intake and bowel rest are often advocated, there is no evidence to suggest that such practice results in increased rates of stula closure, and it may even increase the incidence of complications. Enteral nutrition should be used if possible, although high-output small bowel stulas usually require supplemental parenteral nutrition. Operative repair should be performed when spontaneous closure does not occur, but it should be delayed for at least 3 months.
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