Intestinal Fistulas

Back

Background

A fistula (a term derived from the Latin word for pipe) is an abnormal connection between 2 epithelialized surfaces that usually involves the gut and another hollow organ, such as the bladder, urethra, vagina, or other regions of the gastrointestinal (GI) tract. Fistulas may also form between the gut and the skin or between the gut and an abscess cavity. Rarely, fistulas arise between a vessel and the gut, resulting in profound GI bleeding, which is a surgical emergency. (See Etiology.)

Most GI fistulas (75%-85%) occur as a complication of abdominal surgery. However, 15%-25% of fistulas evolve spontaneously and are usually the result of intra-abdominal inflammation or infection. Regardless of their cause, fistulas have a tremendous impact on patients and society. Increased morbidity and mortality rates, greater health care costs for diagnosis and treatment, prolonged hospital stays, and delayed return to work are just a few direct consequences of this condition. (See Etiology and Prognosis.)

Fistulas were formerly associated with considerable mortality rates. In the decades following the 1960s, however, the introduction of intensive care units (ICUs) and parenteral nutrition lowered the mortality rate to approximately 20%; however, prolonged hospital stays and the high cost of medical and surgical care remained unchanged. In addition, the frequency of fistula formation has not decreased, because of advanced and complicated disease, complex surgical techniques, and an aging population.[1]

Classification

Several classification systems for fistulas exist, none of which are used exclusively. The three most commonly used classification systems are based on anatomic, physiologic (output volume), and etiologic characteristics.[2] Used in combination, these classifications can help to provide an integrated understanding and optimal management scheme for the fistula. (See Etiology, Treatment, and Medication.)

Anatomically, the fistulas are named according to their participating anatomic components, and they can be divided into internal and external fistulas. Internal fistulas connect the GI tract with another internal organ, the peritoneal space, the retroperitoneal space, the thorax, or a blood vessel. External fistulas, which commonly occur postoperatively, are abnormal connections between the GI tract and the skin. (See Presentation.)

Etiology

Risk factors for intestinal fistulas include the following:

Contrary to common belief, fistulas do not necessarily develop as a consequence of downstream stenosis of the intestine. (See the image below.)



View Image

Enterocutaneous fistula after bowel injury from an incisional hernia repair, 6 weeks postinjury.

Gastric fistulas

Gastric fistulas are iatrogenic in most cases (85%). The other cases are usually a consequence of irradiation, malignancy, inflammation, and ischemia. Anastomotic leak after a gastric resection for cancer, peptic ulcer disease, or bariatric surgery can lead to leakage of intestinal or gastric juices, which initiates a cascade of events: localized infection, abscess formation, and, possibly, abscess and fistula formation.

Small bowel fistulas

Nearly 80% of small bowel fistulas result from complications of abdominal surgery. These fistulas may occur from disruption of the anastomotic suture line, inadvertent iatrogenic enterotomy, or small bowel injury at the time of closure. Inadequate blood flow from devascularization or tension at the anastomotic suture lines, anastomosis of diseased bowel, or perianastomotic abscess may compromise the integrity of surgical anastomoses.

Fistulas in Crohn disease

Crohn disease, malignancy, peptic ulcer disease, and pancreatitis spontaneously cause 10%-15% of small bowel fistulas. In patients with Crohn disease, fistulas arise from aphthous ulcers that progress to deep transmural fissures and inflammation, subsequently leading to adherence of the bowel to adjacent structures that eventually penetrate other structures.[3] Microperforation with abscess formation leads to subsequent macroperforation into the adjacent organ or skin, resulting in fistula formation.

Crohn fistulas are more often internal and less commonly external (to the skin). Ileosigmoid fistulas, usually a complication of a diseased terminal ileum that invades the sigmoid colon, are the most common type of fistula between two loops of bowel. Enteroenteric, gastrocolic, duodenocolic, enterovesical, rectovaginal, and perianal fistulas are other potential complications of Crohn disease.[4] Perianal fistulas are the most common external fistulas in patients with Crohn disease. (See the image below.)



View Image

Psoas abscess from Crohn disease that later fistulized to the skin.

Colonic fistulas

Colonic fistulas are primarily a consequence of intra-abdominal inflammation but can also occur after surgical intervention for an inflammatory condition.[5] IBD, diverticulitis, malignancy, and appendicitis (especially with the presence of an appendiceal abscess requiring percutaneous drainage) are the most common inflammatory conditions that lead to colonic fistulas.

Aortoenteric fistulas

Aortoenteric fistulas most commonly occur secondarily, usually after the surgical placement of a graft. Aortoenteric fistulas can develop in the following ways:

Epidemiology

Occurrence in the United States

In developed countries, Crohn disease is the most common cause of spontaneous fistula formation. In their lifetime, as many as 40% of patients with Crohn disease develop a fistula, most often an external or a perianal one.

The incidence of fistula formation in patients with diverticulitis is much lower. Fistula formation complicates diverticulitis in 1%-12% of patients. Colovesical fistulas in men and colovaginal fistulas in women are the most common types of fistulas in this population.

Fistulas can complicate radiation therapy weeks to years after treatment. Radiation therapy for malignancy is associated with fistula formation in approximately 5%-10% of patients.[6] Notably, surgery and anastomosis in previously irradiated tissue increases the risk of anastomotic leak and, subsequently, fistula formation.

International occurrence

Internationally, the frequency of various types of fistulas may vary in correlation with their prevalence in different populations.

For example, the prevalence of fistulas secondary to Crohn disease may be less prevalent in Africa primarily because the disease is less prevalent in that population. However, the prevalence of obstetric fistulas may be higher in developing countries because of obstructed labor (including malpresentation and cephalopelvic disproportion) and lack of prompt access to emergency obstetric care. Accurate prevalence rates of obstetric fistulas are unavailable, likely because of inaccurate reporting of the medical condition and the stigma of its associated symptoms.

Race-, sex-, and age-related demographics

Racial differences in patients with fistulas generally parallel those of the underlying disease or condition that predisposed persons in a specific racial population to developing fistulas. For example, since Crohn disease is more common in whites, patients with Crohn disease who develop fistulas are more likely to be white.

With regard to sex-related prevalences, colovesical fistulas are more common in men and in women who have undergone a hysterectomy. Colovaginal fistulas, of course, occur only in women. Otherwise, fistulas are equally prevalent in males and females.

As with race, age parallels the etiology or underlying condition that predisposes patients to develop fistulas.

Prognosis

The prognosis is based on the etiology of the fistula, as well as the comorbidities of the patient. Pain, wound management, abscess formation, local infection, nutritional deficiencies, and recurrent septic states are just a few of the physical consequences of intestinal fistulas. More recently, it appears that intestinal fistulas may also be associated with impaired coagulation status in patients with Crohn disease.[7]

Patients with fistulas most likely present with much more than physical discomfort and pain. The stigmas of malodorous fistula drainage, malnutrition, and emotional distress also cause significant psychological consequences. In addition, patients with postoperative fistulas have the added distress of lengthy hospital stays, associated morbidity, a delay in returning to work, and restricted social activities. Considerable mortality is associated with fistulas, primarily from sepsis.

In a study of patients who developed fistulas after pancreaticoduodenectomy, specific factors were associated with increased mortality. These factors included fistula site, underlying disease, low hospital volume, the surgeon's experience, high intraoperative blood loss, and complications.[8]

In a retrospective study (2006-2014) that evaluated the disease course and need for surgical intervention in 113 Crohn patients with a penetrating ileal complication, as well as assessed factors related to worse postoperative outcomes, the presence of an abscess was significantly associated with the need for surgery, and there was a five-fold increase in unfavorable postoperative outcomes in patients with low albumin (< 32 g/L).[9]  Overall, more than one third (35%) of patients did not require further medical intervention in the first 5 postoperative years.

Patients who undergo surgery after a failed ligation of the intersphincetric tract (LIFT) procedure have been reported to have 50% healing with placement of a seton followed by fistulotomy or rectal advancement flap.[10]

History and Physical Examination

History

Symptoms caused by fistulas that involve two segments of the bowel vary depending on the location of the fistula and the amount of bowel bypassed. For this reason, enteroenteric fistulas in which only a short segment of bowel is bypassed may be asymptomatic and diagnosed incidentally based on imaging findings or during surgery. Conversely, ileosigmoid fistula may cause diarrhea, weight loss, or abdominal pain.[11]

Patients with gastrocolic fistulas may present with symptoms of abdominal pain, weight loss, and feculent belching.

Enterovesical and colovesical fistulas are easier to diagnose in patients who present with symptoms of pneumaturia, fecaluria, and recurrent urinary tract infections.[12]

Patients with rectovaginal and anovaginal fistulas may be asymptomatic and present with symptoms only when the bowel movements are more liquid. Possible symptoms include inadvertent passage of stool or gas, dyspareunia, and perineal pain. In patients with an anorectal abscess and/or anal fistula, the American Society of Colon and Rectal Surgeons indicates obtaining a thorough disease-specific history with an emphasis on symptoms, risk factors, site, presence of secondary cellulitis, and anal fistula.[13]

Patients with external fistulas generally present with symptoms of drainage through the skin. Patients with aortoenteric fistulas may report rectal bleeding.

Physical examination

Fluid or stool output through the skin, diarrhea, abdominal tenderness, weight loss, signs of malnutrition, and electrolyte imbalances are all possible findings in patients with fistulas.

Rectal bleeding may be a finding in patients with a history of radiation therapy. Hypotension and rectal bleeding may occur in patients with aortoenteric fistulas.

Approach Considerations

Serum tests

Albumin and prealbumin levels should be obtained, as well as blood urea nitrogen (BUN), creatinine, and electrolyte concentrations. These are used to determine the patient's nutritional status and whether fluid or metabolic disturbances are present (more of a concern for high-output fistulas).

Although complete blood cell (CBC) count results may be within the reference range, leukocytosis may be present if an undrained abscess or a continued inflammatory process has developed within a segment of the bowel. Anemia may be present with chronic disease or if a malignant process is involved.

Microbiology

Abscess culture findings may be helpful, especially in the presence of sepsis or ongoing infection (the predominant organism involved being Escherichia coli). Cultures of enterocutaneous fistula output may not be of much clinical use, as normal bowel flora often predominates.

Urinalysis or urine culture

For colovesical fistulas, urinalysis usually reveals increased white blood cell (WBC) count and bacteria levels. Urine culture findings may help to direct antibiotic therapy.

Histology

Histologic findings of fistula site biopsy are usually consistent with chronic inflammation. In patients with Crohn disease as the causative factor, transmural involvement with noncaseating granulomas and lymphoid aggregates throughout the bowel wall may be observed. In patients with carcinoma, inflammation adjacent to the tumor remains a typical finding. The clinical scenario and test results are usually helpful in determining the diagnosis.

Staging

Staging is appropriate when the etiology of the fistula is carcinoma.

Oral administration of nonabsorbable markers

Patients can be given charcoal or Congo red dye orally to verify the presence of an enterocutaneous fistula. However, this is not helpful in determining which portion of bowel is involved. This test is often used in postoperative patients with persistent drainage from a wound in whom an enterocutaneous fistula is suspected or in women with persistent vaginal drainage in whom a rectovaginal fistula is suspected.

Procedures

Endoscopy or colonoscopy

This can be helpful in determining the origin of the bowel disease that caused the fistula, but it is not a particularly helpful or necessary study to reveal a fistula. Biopsy samples may be obtained during the procedure and are useful in diagnosing inflammatory bowel disease (IBD) or Crohn disease and malignancy.

Endoscopy is also under consideration in the management of gastrointestinal transmural defects, such as fistulas.[14, 15]

Fistuloscopy

Although it has been reported and described, fistuloscopy is not a widely used modality for diagnostic and therapeutic use with enteric fistulas. A small-caliber endoscope is passed into the lumen of the fistula in an attempt to identify the source of the fistula. Fistuloscopy may identify abscesses and visualize the bowel involved. Therapeutically, a drain can be placed or fibrin glue sealant may be applied to close the fistula.[16]

Cystoscopy

Useful in the evaluation of suspected enterovesical fistula, cystoscopy may allow visualization of fistulas from within the bladder.

Dye injection

Instilling methylene blue into the rectum and examining a vaginal tampon 15 minutes after placement can often establish the presence of a rectovaginal fistula.

Imaging Studies

In patients with an occult anorectal abscess, complex anal fistula, or perianal Crohn disease, the American Society of Colon and Rectal Surgeons notes computed tomography (CT) scanning, magnetic resonance imaging (MRI), or fistulography should be considered.[13]

CT scanning

Abdominal and pelvic CT scanning is the imaging method of choice to evaluate Crohn disease and possible fistulas. While identification of the fistula is not always possible, CT scanning often reveals perifistular inflammation. This provides additional information regarding the possible etiology of the fistula and the extraluminal involvement of disease.

Revealing abscess cavities or excluding possible sources of sepsis is an important step in the evaluation of patients with suspected fistulas. This information may also prove helpful if surgical intervention is planned. CT angiography (CTA) may be used in the diagnosis of suspected aortoenteric fistulas if the patient is stable.

MRI

Although MRI is reported as an imaging modality that can help identify and characterize enteric fistulas, motion artifact may limit its usefulness, and MRI is not considered a routine adjunctive study in the evaluation of patients with enteric fistulas. T1-weighted images provide information relative to the inflammation in fat planes and possible extension of the fistula relative to the surrounding visceral structures. T2-weighted images can demonstrate fluid collections along the fistula tract and inflammatory changes within the surrounding muscle.

Fistulography

Radiographic study with contrast medium (usually given at the site of fistula output) may be performed to help delineate the extent of the fistula and its communication with the underlying bowel.

Ultrasonography

Ultrasonography can be used in conjunction with physical examination to identify abscesses and fluid collections along the fistula tract. Notably, endoanal ultrasonography has been shown to be superior to digital rectal examination (DRE) for classification of anal fistulae prior to operative intervention.[17]

Barium enema and small bowel series

Contrast studies to evaluate the stomach, small intestine, and colon may reveal a fistula and may also be helpful in determining the cause of fistula formation by identifying diverticular disease, Crohn disease (characteristic string sign), or evidence of malignancy.

Cystography and CT cystography

This procedure can help to evaluate for the presence of a possible enterovesical fistula.[12]

Angiography

Angiography may assist in preoperative planning and evaluation of aortoenteric fistulas in a stable patient or determine the arterial source of bleeding in those with a less common arterioenteric fistula.

Approach Considerations

2016 American Society of Colon and Rectal Surgeons recommendations

Anorectal abscess [13]

Anal fistula [13]

Relatively ineffective treatments for anal fistulas include fistula plugs and fibrin glue.[13]

Perianal fistula associated with Crohn disease [13]

Rectovaginal fistulas [13]

Treatment considerations

Several elements are required to successfully treat patients with an intestinal fistula: adequate nutrition, control and maintenance of the fistula drainage site, appropriate treatment of infection, and avoidance of sepsis.[18, 19, 20]

Spontaneous closure of a proportion of gastrointestinal (GI) fistulas with nonoperative management is well documented. Although dependent on the etiology of the fistula, 60% or more close if they are iatrogenic, if no distal obstruction is present, if no foreign body is involved, if the tract is long, if there is a low output, and if there is no active infection. Numerous studies have delineated the important determinants associated with decreasing the time to closure of a fistula and decreasing a patient's overall associated morbidity and mortality.

Conservative management of enteric fistulas has been described for periods of up to 3 months.[21] One study demonstrated that 90% of the fistulas that spontaneously closed did so within the first month, once management of sepsis had been established.[19] Of note, none of the fistulas spontaneously closed after 3 months.

Factors to consider for fistulas that do not spontaneously close include the following:

In these cases, surgical repair may be the definitive treatment.[22]  (See the image below.) However, it is important to consider the timing of such surgery. A systematic review and meta-analysis of 15 studies regarding the timing and outcome of intestinal failure surgery in patients with enteric fistula found lower recurrence rates in the setting of a longer median time and/or a longer time interval to surgery, and an overall 3% mortality.[23]  The optimal timing for operative intervention could not be defined owing to each study's wide range of time to definitive surgery.



View Image

Status postpancreatic debridement for necrotizing pancreatitis. The patient had a colonic injury with attempted closure using a skin graft. The patien....

Endoscopic managment is also being considered in for gastrointestinal transmural defects, such as fistulas.[14, 15]  In a retrospective study (2015-2016) that assessed the feasibility, safety, and efficacy of endoscopic-guided gastroenterostomy or enteroenterostomy with a lumen-apposing metal stent (LAMS) in 13 patients undergoing reestablishment of bowel continuity following resection and bypass of diseased or obstructed GI tract, investigators reported all patients but one had technical and clinical success.[14]

Enterocutaneous fistulas

A meta-analysis of the literature by Rahbour et al suggested that somatostatin and its analogs are effective in the treatment of enterocutaneous fistulas.[24]  Among patients in the somatostatin group and those in the analog group, fistulas were more likely to close, and to do so faster, than they were in the control group, although comparison with the controls suggested that neither somatostatin nor its analogs affect mortality. Because the risk ratio for somatostatin was higher than that for the somatostatin analogs, it may be that somatostatin can close more fistulas, and do so more quickly, than its analogs.[24]

In a retrospective review of 48 Crohn disease patients with enterocutaneous fistula, Amiot et al found that anti-tumor necrosis factor (anti-TNF) therapy may be effective in up to one third of such patients, particularly those without complex fistulas and stenosis.[25] The study, which had a median follow-up period of 3 years, involved patients with enterocutaneous fistulas of the small bowel, duodenum, or colon (those with perianal fistulas were excluded). Fistulas closed completely in 16 patients (33%), although eight of these individuals relapsed during the follow-up period. Multivariate analysis linked lack of complete fistula closure to the presence of multiple fistula tracts and associated stenosis.[25]

Stem cell therapy, as well as infection of mesenchymal stem cells, appear to have potential in managing refractory perineal Crohn disease.[20, 26, 37]

Consultations

The following consultations can aid in treatment:

Diet

In the initial period, patients are maintained on total parenteral nutrition (TPN) and are given nothing by mouth (NPO).

In patients with low-output, distal fistulas, elemental diets may be initiated as long as they do not profoundly increase the fistula output.

Activity

Aggressive physical therapy provides long-term benefits to patients. Typically, patients do not require prolonged bedrest (which only adds to comorbidities) unless this is necessary for some other reason.

Stabilization

Initial fistula management should address each of the following resuscitation and stabilization issues in patients with a gastrointestinal (GI) fistula.[27]

Nutrition

Total parenteral nutrition (TPN) has long been regarded as an essential therapy (especially in high-output fistulas) to decrease output and to maintain good nutritional status.

Malnutrition is a significant cause of morbidity and mortality, especially with enterocutaneous fistulas. Typically, patients with low-output (< 200 mL per 24 h) fistulas should receive their full resting expenditure, 1-1.5 g of protein/kg daily and a lipid intake that accounts for approximately 30% of daily caloric intake. Patients with high-output (>500 mL per 24 h) fistulas should receive 1.5-2 times their resting energy expenditure, 1.5-2.5 g of protein/kg daily, and twice the recommended daily allowance of lipids.

Skin care and drainage control

Control of enteric contents draining from the fistula continues to be a topic of ongoing research and development. Standard ostomy supplies and other methods of skin care and drainage control can be used in an attempt to reduce or eliminate the persistent tissue inflammation and infection surrounding the fistula, which can lead to sepsis.[28] Use of the vacuum-assisted closure (VAC) device to better manage output has been reported to help improve the perifistular environment.[29] Furthermore, application of VAC with negative pressures up to –125 mm Hg has demonstrated to be effective management prior to surgical treatment.[30]  All of these techniques and devices are used not to close the fistula, but rather to help keep the surrounding tissues healthy and to allow the fistula to heal on its own. Another potential conservative option includes the use of fibrin glue for low-output fistula tracts.[31]  This technique, although not a current standard treatment, has achieved some success in promoting closure of enterocutaneous fistulas.

Identification and drainage of fluid collections

The use of computed tomography (CT) scanning and ultrasonography can help to determine if fluid collections or abscesses are present along the abscess tract. Identification of these fluid collections often allows for CT-guided drainage of these loci to prevent infection. Along with better drainage control and appropriate antibiotic treatment, this helps to decrease the morbidity and mortality associated with enteric fistulas and allows for a safer period of conservative management. Radiologically placed catheters have been demonstrated to safely and successfully drain most abscesses.

Fluid volume depletion

In patients with proximal, high-output fistulas, the volume depletion associated with the drainage can be a significant problem. Whether medications such as octreotide (a synthetic substitute of somatostatin that suppresses the release of many GI hormones) help to close fistulas remains unclear.[32] Research has demonstrated significant and nonsignificant effects of medication on the closure of fistulas, yet these studies agree that octreotide does decrease overall fistula output.[32]

Resection and Anastomosis

The period of nonoperative management of an enteric fistula, while allowing for spontaneous closure of the fistula, also provides time to optimize nutritional status and to heal the wound site from the patient's initial surgery (if the enteric fistula occurred postoperatively). Thus, definitive surgery for fistula repair is generally delayed for several months until physiologic deficits have been restored and intra-abdominal conditions are less hostile. However, if diffuse peritonitis with ongoing sepsis is observed, immediate operative exploration may be necessary to stabilize the patient.

The preferred procedure involves excision of the fistula tract, with segmental resection of involved bowel and anastomosis of the remaining bowel.[33] If an unexpected abscess is encountered or the quality of the bowel wall is suboptimal, some surgeons may consider a primary anastomosis unsafe, instead choosing to perform a staged procedure, with exteriorization of the ends of the bowel during the first procedure. A staged repair may also be more appropriate in cases in which advanced malignancy or severe radiation changes are expected. If the procedure is performed for a malignancy, preferably, the involved segment of bowel is removed to negative margins.

The abdominal wall may not be able to be closed due to a lack of fascia. In these cases, biologic meshes, which are manufactured from porcine or bovine dermis, human cadaveric dermis, or porcine small intestinal submucosa, may be used to help close the abdominal cavity. These meshes are not at risk for infection.

Perianal abscesses should be drained and anal strictures dilated. Patients with low anal fistulas can be treated with fistulotomy. Some surgeons are in favor of a noncutting seton, especially in the presence of an active inflammation of the rectosigmoid colon. Noncutting setons may be placed in fistula tracts in patients with rectal inflammation, and endorectal advancement flap procedures for high perianal fistulas and rectovaginal fistulas may be performed in patients without rectal inflammation. Another option that preserves sphincteric function is using a fistula plug, which provides a matrix for soft-tissue healing.[34, 35]

If a rectovaginal fistula persists after the patient has received medical therapy and anorectal stricture or active rectal disease is not evident, then surgical repair may be performed with either (1) transanal or transvaginal advancement flaps or (2) laparotomy with primary closure or sleeve advancement flap.[36]

Patients with colovesical fistulas can almost always be treated with resection of the involved segment of colon and primary reanastomosis, with or without closure of the bladder defect. Healing of the bladder is usually managed easily with temporary urethral catheter drainage.

The overall incidence of aortoenteric fistulas has changed with the advent of endovascular repairs of abdominal aortic aneurysms, but the criterion standard remains open excisional repair and extra-anatomic bypass for revascularization in the case of secondary aortoenteric fistulas (which occur after open repair of abdominal aortic aneurysms). Endovascular repair of primary aortoenteric fistulas in high-risk patients (ie, those at risk for chronic infection of the endograft) has been reported.

Complications

Intestinal fistulas carry high morbidity and mortality rates. If medical and nonoperative treatments are not effective, the risks of surgery need to be discussed with patients and their families.

Complications are routine, as dense, fibrotic adhesions are likely to be encountered during surgery. Infection, bleeding, and injury to adjacent organs, as well as recurrence of the fistula, are all possibilities. To reduce these complications, patients must receive optimal nutrition and must be treated by an experienced surgeon.

Follow-up

Follow-up care is based on disease etiology. In patients with chronic inflammatory conditions, such as Crohn disease, ongoing follow-up care is required.

If patients are simply waiting for definitive surgical therapy and being maintained on total parenteral nutrition, they do not need to be in the hospital. Home infusion or placement in a rehabilitation facility is perfectly acceptable. Close contact is needed, as line sepsis and other infectious complications may occur, and early and aggressive treatment is essential to ensure a good outcome.

In patients who have undergone surgical repair, normal postoperative follow-up care is required. Once the incisions are healed and the drains are removed, the patient may be discharged from care.

Patients with Crohn disease may require ongoing outpatient maintenance therapy with medication.

Medication Summary

As previously stated, it is not yet clear whether medications such as octreotide (a synthetic substitute of somatostatin that suppresses the release of many gastrointestinal hormones) help to close fistulas. Although contradictory findings on the role of medication in fistula closure have been found, research has shown that octreotide decreases overall fistula output.[32] Immunosuppressive agents used in fistula therapy include azathioprine and infliximab.

A 2015 published report highlighted the potential use for serial intrafistular injections of autologous bone marrow-derived mesenchymal stem cells (MSCs) in patients with refractory Crohn fistulas.[37] As determined by this phase I-II study of a small group of patients, the use of locally injected MSCs was safe and efficacious and further benefited patient outcomes through rescue of previously ineffective treatments.[37] Although not a current standard of care, these results provide intriguing insights into future novel therapies.

Octreotide (Sandostatin)

Clinical Context:  Octreotide is an inhibitory hormone consisting of 2 peptides (14 amino acids and 28 amino acids in length) secreted by hypothalamus and delta cells of the stomach, intestines, and pancreas. It inhibits the release of growth hormone (GH) and thyroid-stimulating hormone (TSH) and suppresses the release of many GI hormones (gastrin, cholecystokinin, secretin, motilin, vasoactive intestinal polypeptide [VIP], glucose-dependent insulinotropic polypeptide [GIP]).

Octreotide results in decreased gastric emptying and reduces smooth muscle contractions and blood flow in the intestines. It is approved for use in treating acromegaly (since it blocks GH release) and symptoms related to carcinoid syndrome and VIPomas.

Class Summary

These agents inhibit the release of serotonin and the secretion of many hormones involved in GI function.

Azathioprine (Imuran, Azasan)

Clinical Context:  Azathioprine is a prodrug that is converted in the body to 6-mercaptopurine (6-MP). A member of a group of medicines called antimetabolites, azathioprine is a chemotherapy medication that inhibits the activity of the immune system, consequently reducing inflammation. Originally developed to treat certain forms of leukemia, the drug has been used to treat some conditions in which the immune system is overly active, such as Crohn disease. Clinical studies of azathioprine therapy have demonstrated a significant improvement in closure rates or improvement of the fistula site compared with placebo.

Infliximab (Remicade)

Clinical Context:  Infliximab is a monoclonal antibody with murine variable regions that specifically bind human tumor necrosis factor alpha (TNF-alpha), which has important role in promoting inflammation. By blocking the action of TNF-alpha, infliximab reduces signs and symptoms of inflammation. Clinical studies have demonstrated that infliximab significantly improved closure rates of fistulas in patients with Crohn disease and was as effective as maintenance therapy in reducing the number of relapses compared with previous medical treatment therapies.

Class Summary

These agents inhibit the activity of key factors in the immune system.[38]

Author

David E Stein, MD, Professor and Alma Dea Morani Chair of Surgery, Director, Mini-Medical School Program, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Asyia S Ahmad, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Associate Program Director, Gastroenterology and Hepatology Fellowship Training Program, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Rebecca B Hasley, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Burt Cagir, MD, FACS, Clinical Professor of Surgery, The Commonwealth Medical College; Director, General Surgery Residency Program, Robert Packer Hospital; Attending Surgeon, Robert Packer Hospital and Corning Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Radha V Menon, MD, Resident Physician, Department of Internal Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Christopher K Chiu, MD Staff Physician, Department of General Surgery, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References

  1. Elliott TB, Yego S, Irvin TT. Five-year audit of the acute complications of diverticular disease. Br J Surg. 1997 Apr. 84 (4):535-9. [View Abstract]
  2. Berry SM, Fischer JE. Classification and pathophysiology of enterocutaneous fistulas. Surg Clin North Am. 1996 Oct. 76 (5):1009-18. [View Abstract]
  3. Kyle J. Fistulae in Crohn's disease. In: Lee ECG, Nolan DJ, eds. Clinical Surgery International: Surgery of Inflammatory Bowel Disorders. Avon, CT: Churchill Livingston; 1987. Vol 14: 190-6.
  4. Annibali R, Pietri P. Fistulous complications of Crohn's disease. Int Surg. 1992 Jan-Mar. 77 (1):19-27. [View Abstract]
  5. Lavery IC. Colonic fistulas. Surg Clin North Am. 1996 Oct. 76 (5):1183-90. [View Abstract]
  6. Donner CS. Pathophysiology and therapy of chronic radiation-induced injury to the colon. Dig Dis. 1998 Jul-Aug. 16 (4):253-61. [View Abstract]
  7. Li Y, Ren JA, Wang GF, et al. Impaired coagulation status in the Crohn's disease patients complicated with intestinal fistula [Chinese]. Chin Med J (Engl). 2018 Mar 5. 131 (5):567-73. [View Abstract]
  8. Bottger TC, Junginger T. Factors influencing morbidity and mortality after pancreaticoduodenectomy: critical analysis of 221 resections. World J Surg. 1999 Feb. 23 (2):164-71; discussion 171-2. [View Abstract]
  9. Bossuyt P, Debeuckelaere C, Ferrante M, et al. The operative risk and natural history after the diagnosis of ileal penetrating Crohn's disease. Eur J Gastroenterol Hepatol. 2018 Feb 16. [View Abstract]
  10. Wright M, Thorson A, Blatchford G, Shashidharan M, Beaty J, Bertelson N, et al. What happens after a failed LIFT for anal fistula?. Am J Surg. 2017 Dec. 214 (6):1210-3. [View Abstract]
  11. Falconi M, Pederzoli P. The relevance of gastrointestinal fistulae in clinical practice: a review. Gut. 2001 Dec. 49 Suppl 4:iv2-10. [View Abstract]
  12. Pontari MA, McMillen MA, Garvey RH, Ballantyne GH. Diagnosis and treatment of enterovesical fistulae. Am Surg. 1992 Apr. 58 (4):258-63. [View Abstract]
  13. [Guideline] Vogel JD, Johnson EK, Morris AM, et al. Clinical practice guideline for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. Dis Colon Rectum. 2016 Dec. 59 (12):1117-33. [View Abstract]
  14. Amateau SK, Lim CH, McDonald NM, Arain M, Ikramuddin S, Leslie DB. EUS-guided endoscopic gastrointestinal anastomosis with lumen-apposing metal stent: feasibility, safety, and efficacy. Obes Surg. 2018 Mar 2. [View Abstract]
  15. Bemelman WA, Baron TH. Endoscopic management of transmural defects (leaks/perforations/fistulae). Gastroenterology. 2018 Feb 15. [View Abstract]
  16. Rots WI, Mokoena T. Successful endoscopic closure of a benign gastrocolonic fistula using human fibrin sealant through gastroscopic approach: a case report and review of the literature. Eur J Gastroenterol Hepatol. 2003 Dec. 15 (12):1351-6. [View Abstract]
  17. Sirikurnpiboon S, Phadhana-anake O, Awapittaya B. Comparison of endoanal ultrasound with clinical diagnosis in anal fistula assessment. J Med Assoc Thai. 2016 Feb. 99 Suppl 2:S69-74. [View Abstract]
  18. Hancock BD. ABC of colorectal diseases. Haemorrhoids. BMJ. 1992 Apr 18. 304 (6833):1042-4. [View Abstract]
  19. Rolandelli R, Roslyn JJ. Surgical management and treatment of sepsis associated with gastrointestinal fistulas. Surg Clin North Am. 1996 Oct. 76 (5):1111-22. [View Abstract]
  20. Panes J, Rimola J. Perianal fistulizing Crohn's disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol. 2017 Nov. 14 (11):652-64. [View Abstract]
  21. Pederzoli P, Bassi C, Falconi M, Albrigo R, Vantini I, Micciolo R. Conservative treatment of external pancreatic fistulas with parenteral nutrition alone or in combination with continuous intravenous infusion of somatostatin, glucagon or calcitonin. Surg Gynecol Obstet. 1986 Nov. 163 (5):428-32. [View Abstract]
  22. Wedell J, Banzhaf G, Chaoui R, Fischer R, Reichmann J. Surgical management of complicated colonic diverticulitis. Br J Surg. 1997 Mar. 84 (3):380-3. [View Abstract]
  23. de Vries FEE, Atema JJ, van Ruler O, Vaizey CJ, Serlie MJ, Boermeester MA. A systematic review and meta-analysis of timing and outcome of intestinal failure surgery in patients with enteric fistula. World J Surg. 2018 Mar. 42 (3):695-706. [View Abstract]
  24. Rahbour G, Siddiqui MR, Ullah MR, Gabe SM, Warusavitarne J, Vaizey CJ. A meta-analysis of outcomes following use of somatostatin and its analogues for the management of enterocutaneous fistulas. Ann Surg. 2012 Dec. 256 (6):946-54. [View Abstract]
  25. Amiot A, Setakhr V, Seksik P, et al. Long-term outcome of enterocutaneous fistula in patients with Crohn's disease treated with anti-TNF therapy: a cohort study from the GETAID. Am J Gastroenterol. 2014 Sep. 109 (9):1443-9. [View Abstract]
  26. Wainstein C, Quera R, Fluxa D, et al. Stem cell therapy in refractory perineal Crohn's disease: long-term follow-up. Colorectal Dis. 2018 Jan 6. [View Abstract]
  27. Levy C, Tremaine WJ. Management of internal fistulas in Crohn's disease. Inflamm Bowel Dis. 2002 Mar. 8 (2):106-11. [View Abstract]
  28. Sahnan K, Askari A, Adegbola SO, et al. Natural history of anorectal sepsis. Br J Surg. 2017 Dec. 104 (13):1857-65. [View Abstract]
  29. Goverman J, Yelon JA, Platz JJ, Singson RC, Turcinovic M. The "Fistula VAC," a technique for management of enterocutaneous fistulae arising within the open abdomen: report of 5 cases. J Trauma. 2006 Feb. 60 (2):428-31; discussion 431. [View Abstract]
  30. Terzi C, Egeli T, Canda AE, Arslan NC. Management of enteroatmospheric fistulae. Int Wound J. 2014 Jun. 11 Suppl 1:17-21. [View Abstract]
  31. Wu X, Ren J, Wang G, et al. Evaluating the use of fibrin glue for sealing low-output enterocutaneous fistulas: study protocol for a randomized controlled trial. Trials. 2015 Oct 7. 16:445. [View Abstract]
  32. Dorta G. Role of octreotide and somatostatin in the treatment of intestinal fistulae. Digestion. 1999. 60 suppl 2:53-6. [View Abstract]
  33. Greenstein AJ. The surgery of Crohn's disease. Surg Clin North Am. 1987 Jun. 67 (3):573-96. [View Abstract]
  34. van Koperen PJ, Bemelman WA, Gerhards MF, et al. The anal fistula plug treatment compared with the mucosal advancement flap for cryptoglandular high transsphincteric perianal fistula: a double-blinded multicenter randomized trial. Dis Colon Rectum. 2011 Apr. 54 (4):387-93. [View Abstract]
  35. Buchberg B, Masoomi H, Choi J, Bergman H, Mills S, Stamos MJ. A tale of two (anal fistula) plugs: is there a difference in short-term outcomes?. Am Surg. 2010 Oct. 76 (10):1150-3. [View Abstract]
  36. Zhu YF, Tao GQ, Zhou N, Xiang C. Current treatment of rectovaginal fistula in Crohn's disease. World J Gastroenterol. 2011 Feb 28. 17 (8):963-7. [View Abstract]
  37. Ciccocioppo R, Gallia A, Sgarella A, Kruzliak P, Gobbi PG, Corazza GR. Long-term follow-up of Crohn disease fistulas after local injections of bone marrow-derived mesenchymal stem cells. Mayo Clin Proc. 2015 Jun. 90 (6):747-55. [View Abstract]
  38. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 1999 May 6. 340 (18):1398-405. [View Abstract]
  39. Ellis CN. Sphincter-preserving fistula management: what patients want. Dis Colon Rectum. 2010 Dec. 53 (12):1652-5. [View Abstract]
  40. Lindberg E, Järnerot G, Huitfeldt B. Smoking in Crohn's disease: effect on localisation and clinical course. Gut. 1992 Jun. 33 (6):779-82. [View Abstract]
  41. Meissner K. Late radiogenic small bowel damage: guidelines for the general surgeon. Dig Surg. 1999. 16 (3):169-74. [View Abstract]
  42. [Guideline] The Standards Practice Task Force of The American Society of Colon and Rectal Surgeons. Practice parameters for treatment of fistula-in-ano--supporting documentation. Dis Colon Rectum. 1996 Dec. 39 (12):1363-72. [View Abstract]
  43. Schecter WP. Management of enterocutaneous fistulas. Surg Clin North Am. 2011 Jun. 91 (3):481-91. [View Abstract]
  44. Jiang H, Shen J, Ran Z. Epithelial-mesenchymal transition in Crohn's disease. Mucosal Immunol. 2017 Dec 20. [View Abstract]
  45. Sheldon R, Eckert M. Surgical critical care: gastrointestinal complications. Surg Clin North Am. 2017 Dec. 97 (6):1425-47. [View Abstract]

Enterocutaneous fistula after bowel injury from an incisional hernia repair, 6 weeks postinjury.

Psoas abscess from Crohn disease that later fistulized to the skin.

Status postpancreatic debridement for necrotizing pancreatitis. The patient had a colonic injury with attempted closure using a skin graft. The patient later underwent definitive repair.

Enterocutaneous fistula after bowel injury from an incisional hernia repair, 6 weeks postinjury.

Status postpancreatic debridement for necrotizing pancreatitis. The patient had a colonic injury with attempted closure using a skin graft. The patient later underwent definitive repair.

Psoas abscess from Crohn disease that later fistulized to the skin.