IMPROVING OUTCOMES IN PATIENTS WITH ANASTOMOTIC LEAK FOLLOWING ESOPHAGECTOMY By Megan Dibble A thesis submitted to the School of Radiologic Sciences in collaboration with a research agenda team In partial fulfillment of the requirements for the degree of MASTER OF SCIENCE IN RADIOLOGIC SCIENCES (MSRS) WEBER STATE UNIVERSITY Ogden, Utah December 15, 2023 THE WEBER STATE UNIVERSITY GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Megan Dibble This thesis has been read by each member of the following supervisory committee and by a majority vote found to be satisfactory. ______________________________ Dr. Robert Walker, PhD Chair, School of Radiologic Sciences ______________________________ Dr. Laurie Coburn, EdD Director of MSRS RA ______________________________ Dr. Tanya Nolan, EdD Director of MSRS ______________________________ Christopher Steelman, MS Director of MSRS Cardiac Specialist Abstract This literature review examines the patient factors that increase the risk of anastomotic leak, it explains how esophagectomies are performed as well as techniques that can be employed to reduce anastomotic complications. Clinical and diagnostic methods for detecting anastomotic leaks are studied, and treatments along with new advancements on the topic are discussed. An esophagectomy is a procedure that is commonly used to treat cancer or other benign pathology of the esophagus. A leak in the surgical anastomosis following esophagectomy is a risk that has the potential to cause significant morbidity and mortality among patients. This literature review of recent articles and research focuses on adults who developed an anastomotic leak following an esophagectomy to investigate ways to improve patient outcomes. Although there have been many advancements on this topic, many aspects of anastomotic leak are still being debated. Current practice is tailored to individual patients but there is a need for future research to establish clinical guidelines for management of anastomotic leaks. Table of Contents Chapter 1: Introduction .................................................................................................... 6 Background................................................................................................................. 7 Statement of the Problem ............................................................................................ 8 Purpose of the Study ................................................................................................... 9 Research Questions ..................................................................................................... 9 Nature of the Study ................................................................................................... 10 Definition of Key Terms ........................................................................................... 10 Summary .................................................................................................................. 11 Chapter 2: Clinical Background ..................................................................................... 12 Introduction .............................................................................................................. 12 Etiology .................................................................................................................... 13 Epidemiology............................................................................................................ 14 Pathophysiology ....................................................................................................... 15 History and Physical ................................................................................................. 16 Evaluation................................................................................................................. 17 Treatment / Management Options ............................................................................. 18 Complications ........................................................................................................... 19 Summary .................................................................................................................. 20 Chapter 3: Literature Reviews ....................................................................................... 21 Documentation.......................................................................................................... 21 General Literature Review ........................................................................................ 21 Patient-Related Factors ............................................................................................. 21 Nutrition............................................................................................................... 21 Smoking and Alcohol Use .................................................................................... 22 Chemotherapy and Radiation................................................................................ 22 Hypotension ......................................................................................................... 23 Blood Transfusions .............................................................................................. 23 Comorbidities ....................................................................................................... 24 Surgical Techniques .................................................................................................. 24 Choice of Conduit ................................................................................................ 25 Transthoracic (Ivor Lewis) Esophagectomy .......................................................... 25 Transthoracic 3 Incision (McKeown) Esophagectomy .......................................... 26 Transhiatal (Orringer) Esophagectomy ................................................................. 26 Diagnosis of Anastomotic Leaks ............................................................................... 27 Clinical Signs and Drain Analysis ........................................................................ 27 Laboratory Markers .............................................................................................. 27 Contrast Esophagram ........................................................................................... 28 Computed Tomography ........................................................................................ 29 Endoscopy............................................................................................................ 30 Treatments ................................................................................................................ 30 Conservative Methods .......................................................................................... 30 Endoscopy............................................................................................................ 31 Surgery................................................................................................................. 32 Summary .................................................................................................................. 32 Case Study Literature Review ................................................................................... 33 Preoperative Patient Selection and Preconditioning ................................................... 33 Arterial Calcification Detection ............................................................................ 33 Ischemic Gastric Preconditioning ......................................................................... 33 Surgical Techniques .................................................................................................. 34 Choice of Conduit ................................................................................................ 34 Surgical Technique Leak Rates............................................................................. 34 Robotic Esophagectomy ....................................................................................... 35 Omentoplasty ....................................................................................................... 36 Stapled or Handsewn Anastomosis ....................................................................... 36 Detection of Anastomotic Leaks ............................................................................... 37 Contrast Esophagram and Computed Tomography ............................................... 37 Treatment Options .................................................................................................... 39 Interventional Radiography .................................................................................. 39 Bovine Pericardial Patch Repair ........................................................................... 40 Sternocleidomastoid Flap Repair .......................................................................... 41 Summary .................................................................................................................. 41 Chapter 4: Research Method .......................................................................................... 42 Research Method ...................................................................................................... 42 Population................................................................................................................. 43 Sample ...................................................................................................................... 43 Limitations................................................................................................................ 43 Delimitations ............................................................................................................ 43 Summary .................................................................................................................. 43 Chapter 5: Findings ....................................................................................................... 45 Results ...................................................................................................................... 45 Evaluation of Findings .............................................................................................. 51 Summary .................................................................................................................. 52 Chapter 6: Implications, Recommendations, and Conclusions ........................................ 54 Implications .............................................................................................................. 54 Recommendations ..................................................................................................... 55 Conclusions .............................................................................................................. 58 References ..................................................................................................................... 60 7 Chapter 1: Introduction An esophagectomy is a surgical procedure employed to treat cancers or benign pathologies of the esophagus.1 The surgery is performed by removing all or part of the esophagus which is then rebuilt using the stomach, small intestine, or large bowel.1 An anastomosis is the surgical connection between these two hollow structures.2 A leak in this connection is called an anastomotic leak, and this has been defined as “A defect of the integrity in a surgical join between two hollow viscera with communication between the intraluminal and extraluminal compartments.”3 As in most procedures, an esophagectomy has potential for complications. A leak at the anastomosis site is a risk for patients who have potential for a poor prognosis.4 Leaks can occur at any location of the gastrointestinal tract during surgery, but the esophagus has the highest degree of leakage of any site at a rate of 9.6% to 14%.5 There are many factors that influence a person’s risk of developing an anastomotic leak. Patient variables such as the use of chemotherapy, a patient’s overall health, patient age, lifestyle factors, etc. are considerations that should be evaluated, and when adjustable, should be modified to reduce threat of a leak at the anastomoses site. 5 However, there are patient factors that are not modifiable, such as the location of the anastomosis. Surgical planning and techniques can be used to mitigate these risks to decrease likelihood that a leak may develop.6,7 An anastomotic leak can be detected by changes in clinical presentation and lab values or through diagnostic imaging tests such as computed tomography or contrast esophagram.8 Imaging can either visualize the leak itself or demonstrate other pathology 8 that would suggest an anastomotic leak.9 Endoscopy is also an option that can both detect a leak and perform various treatment options during the same procedure.10,11 Once an anastomotic leak is identified, there are different ways it can be managed.5 Conservative measures, endoscopy, interventional radiology, or surgery are all potential treatment options depending on the severity and location of the leak.12,3 Once a person has developed an anastomotic leak, prompt detection and treatment is imperative for a successful outcome.13 The patient’s prognosis is negatively affected by a delayed diagnosis and this can lead to complications, prolonged hospital stays and clinical burden.13 Background According to the American Cancer Society, about 21,560 new cases of esophageal cancer will be diagnosed in 2023. 14 The lifetime risk of esophageal cancer in the United States is about 1 in 125 men and about 1 in 417 women with a 20% rate of survival five years after diagnosis.14 The two main types of cancer that affect the esophagus are squamous cell carcinoma and adenocarcinoma. 15 Squamous cell carcinoma forms in the inner mucosal layer of the esophagus and makes up approximately 30% of esophageal cancers.15 It can occur anywhere along the esophagus, however, this cancer often occurs in the upper (cervical) region and in the middle (thoracic) region.15 Adenocarcinomas begin in the gland cells of the esophagus and they are most often found in the lower third of the (thoracic) esophagus.15 Other less common forms of esophageal cancer include lymphomas, melanomas, and sarcomas. 15 In addition to esophageal cancer treatment, an esophagectomy can be an option for patients who have lost function of the esophagus creating a poor quality of life.16 9 Benign neoplasms such as gastrointestinal stromal tumors, leiomyomas, schwannoma, granular cell tumors, papillomas, fibrovascular polyps, and adenomas, among others, may warrant an esophagectomy if the mass causes obstruction of the esophagus or compression of the mediastinal structures.16 Dysmotility of the esophagus caused by diseases such as achalasia, scleroderma, or even esophageal spasm may severely interfere with the physiologic movement of the esophagus to the point that an esophageal resection is necessary.16 Additionally, traumas to the esophagus, possibly due to ingestion of caustic agents or esophageal perforation due to Boerhaave’s syndrome, external, or iatrogenic trauma may also rarely require an esophagectomy.16 An anastomotic leak remains the most feared complication of an esophagectomy, but in spite of research efforts, the causal factors and pathophysiology surrounding anastomotic leaks remains unclear.13 Current clinical and surgical research is centered around areas of prevention and early diagnosis but experimentation is risky due to the severe nature of the potential complications.3 Statement of the Problem A leak at the anastomosis site after esophagectomy is a risk that, despite advances in surgical and management techniques, continues to have the potential to cause significant morbidity, mortality, prolonged hospital stays, considerable costs, and decreased quality of life.4 Even when an anastomotic leak has been treated, long-term consequences such as anastomotic strictures can arise, further complicating a patient’s health.6 Anastomotic leak of the esophagus has a complex etiology with multifactorial components. Research and guidelines need to be made to help with patient selection and to improve surgical outcomes. There is little research about the best way to diagnose an 10 anastomotic leak and technical training is imperative to performing sensitive exams. Additionally, anastomotic leak treatment is currently focused on an individual basis.13 Evidence-based guidelines are urgently needed to improve patient outcomes. 13 Purpose of the Study The purpose of this literature review is to explore information pertaining to anastomotic leaks following esophagectomy. General insights about this topic will help to inform readers about patient factors that can increase the risk of anastomotic leak development. The study will also be informative as to how an esophagectomy is performed and what clinical factors may indicate suspicion of an anastomotic leak after surgery. The study will help to explain the various ways that an anastomotic leak can be diagnosed as well as the possible options that can be employed for treatment. New advances in the field will also be explored. Anastomotic leaks can cause severe morbidity and mortality, and it may require the expertise of many specialties to treat a patient that develops this problem.4 Understanding the entirety of the process and performing more research on the topic may help to improve patient outcomes. Research Question Q1. What patient factors can be identified that may be increase the risk for the development of an anastomotic leak? Q2. How are esophagectomies performed and what techniques can be used to reduce the risk of anastomotic leaks? Q3. What are some methods for detecting an anastomotic leak and when should these be employed? Are there any new ways to detect leaks that are being tested? 11 Q4. How are anastomotic leaks treated and are there any new advancements in this area? Nature of the Study To explore the collective evidence about the best practices in preventing, diagnosing, and managing anastomotic leaks of the esophagus, a literature review of articles pertaining to patient factors, surgical methods, diagnostic tools, and treatment methods was performed. Anastomotic leaks of the esophagus continue to occur at high rates following esophagectomy and patients often have a poor prognosis when leaks occur. The potential contribution of this review is to help educate healthcare professionals, in particular, radiology imaging professionals about ways to improve outcomes in patients with anastomotic leaks. Research was done to provide information about patient selection and modifiable risk factors as well as the location of potential anastomotic leaks depending on the type of surgery performed. Diagnostic tools such as contrast esophagram, computed tomography and endoscopy are explored, and current treatment options are discussed. This literature review was conducted by selecting articles and research studies written within the last 10 years to discover current practices and emerging trends that promote favorable outcomes in patients undergoing esophagectomy. Definition of Key Terms Esophagectomy. An esophagectomy is a surgical procedure used to remove some or all of the esophagus followed by reconstruction using part of another organ, usually the stomach. Esophagectomy is a common treatment for 12 advanced esophageal cancer and is used occasionally to remove precancerous cells or to treat other non-cancerous conditions.17 Anastomosis. An anastomosis is a surgical connection between two tubular structures where the two remaining ends are sewn or stapled together (anastomosed).2 Anastomotic Leak. A defect of the integrity in a surgical join between two hollow viscera with communication between the intraluminal and extraluminal compartments.3 Summary Esophagectomy is a surgery performed to treat benign and malignant pathology of the esophagus. Anastomotic leaks are a risk that have the potential to cause significant morbidity and mortality. This literature review aims to provide information regarding patient risk factors, surgical techniques, diagnostic tests, treatments, and advancements related to anastomotic leaks following esophagectomy to improve patient outcomes. 13 Chapter 2: Clinical Background Introduction An anastomotic leak after esophagectomy is a defect in the surgical connection between the remaining portion of the esophagus and the chosen conduit whether gastric, jejunal, or colonic.1,2 Anastomotic leaks occur most frequently in the esophagus compared with other locations in the gastrointestinal tract at a rate as high as 9.6%-14%.5 The risk of anastomotic leak can be increased by patient factors such as the patient’s sex, malnourishment, smoking and alcohol use, chemotherapy and radiation, and comorbidities such as diabetes mellitus, hypertension, peripheral artery disease, and heart disorders.18 Surgical techniques, the choice of conduit chosen, and the site of the anastomosis all carry variable levels of risk for a leak as well. An anastomotic leak may be asymptomatic, or it may have clinical signs such as tachycardia, arrythmia, leukocytosis, respiratory failure, subcutaneous emphysema, chest pain, pneumothorax, pleural effusion, redness and swelling to the incisions, or a change of surgical drain contents.19 Suspicion of an anastomotic leak can be confirmed by laboratory markers, endoscopy, or with imaging such as esophagram or computed tomography.20 Once a diagnosis is made, the severity of the leak will determine the required treatment. 20 Anastomotic leak can be managed conservatively, or it may require treatment with endoscopy or surgical intervention.20 Anastomotic leaks can create complications that 14 have the potential to lead to prolonged hospitalization, decreased quality of life, and reduced life expectancy.21 Etiology There are a multitude of factors that can increase the incidence of an anastomotic leak and a clear or specific cause can rarely be established. Preoperative patient factors and comorbidities, surgical techniques, and postoperative protocols can all influence how an anastomosis will heal. The esophagus, rectum, and pancreas have the highest rates of anastomotic leaks within the gastrointestinal tract. None of these organs possess a serosa, the lining that surrounds other organs in the GI tract. The serosal layer might provide some protection or strength to an anastomosis that is not well understood.18 Additionally, the esophagus and rectum, the two organs with the highest rate of anastomotic leak tend to have slightly higher tension on the tissues which can increase the rate of anastomotic dehiscence.18 Patient-related considerations that have been identified as risk factors for anastomotic leak include the patient’s sex, malnourishment, smoking and alcohol use, chemotherapy and radiation, and comorbidities such as diabetes mellitus, hypertension, peripheral artery disease and heart disorders.18 Men tend to have higher rates of anastomotic leaks than women.18 Nutritionally depleted patients, which may affect up to 80% of cancer patients, are at a higher risk of developing an anastomotic leak. 7,18 Daily smokers have an increased risk of pulmonary and wound complications with a four-fold associated risk of anastomotic leak, and alcohol abusers similarly have increased hemorrhagic, wound, and cardiopulmonary risks.7 Chemotherapy drugs can negatively affect wound healing by attenuating the function of the immune system. 3 Specifically, 15 new forms of chemotherapy, including vascular endothelial growth factor inhibitors (bevacizumab) have been shown to increase late anastomotic leaks. 5 In terms of radiation of the esophagus, some studies suggest there is no correlation to increased anastomotic leak rates, but others suggest that higher doses of radiation to a cervical anastomosis can increase the risk of a leak.5 Comorbidities can affect the postoperative wound healing and increase the risk of a leak at the anastomosis site. Defective glucose control with diabetes, for example, leads to vascular damage and decreased blood flow as well as toxic glucosederived products accumulating within the cells. 3 The surgical approach and techniques can also influence an anastomotic leak. 18 The conduit chosen to replace the esophagus during an esophagectomy may include either the stomach, small intestine, or colon.7 These organs are all structurally different and require changes in surgical approach which can affect the rate of a leak at the anastomosis.6 There are three different surgical methods used to perform an esophageal resection: transthoracic Ivor Lewis esophagectomy, transthoracic 3 incision McKeown esophagectomy, or transhiatal Orringer esophagectomy. 22 These all differ in their rate of anastomotic leak with the transhiatal having the most increased risk.23 Epidemiology Anastomotic leak is a highly feared complication of esophagectomy. However, understanding the incidence of anastomotic leaks has been challenging because there has not been an accepted definition or standard method for recording or tracking complications. In 2011, the Esophageal Complications Census Group (ECCG) was formed to create a basic platform of complications that should be reported in outcome studies and they developed an infrastructure defining the four critical individual 16 complications, which includes anastomotic leaks.24 ESODATA.org was created by the ECCG to collect perioperative data from surgical centers that perform esophagectomies. 25 In 2022, a study was released with over 6000 cases on behalf of the International Esodata Study Group which helped compare data from two different time periods 2015-2016 and 2017-2018.26 This study demonstrated that anastomotic leak rates increased from 11.7% to 13.1% which is consistent with other published trends. Despite this increase, the rate of leaks that required surgical treatment remained unchanged. 26 Esophageal resection is most often performed as a treatment for esophageal cancer, which has been rapidly increasing in recent decades.27 Due to a global aging population and prevalence of risk factors such as poor diet, obesity, and tobacco and alcohol consumption, incidence and mortality is increasing from this disease which will in turn potentially increase the incidence of anastomotic leaks.27 Pathophysiology An anastomosis is a surgical connection, that like other wounds, goes through phases of healing that may last up to a year. 3 Healing immediately begins with hemostasis or fibrin clot formation to control bleeding at the site.3 This is followed by a period of inflammation that generally lasts up to 10 days where white blood cells clean up the site by removing debris, toxins, and microorganisms.3 Then begins the proliferative phase that lasts between 5-21 days where fibroblasts, endothelial cells, myofibroblasts, and epithelial cells reconstitute the stroma and re-epithelialize the site.3 In the final phase, which can take up to a year, remodeling of collagen and vasculature 17 occurs by the stromal cells.3,28 Unfortunately, the average healed wound only reaches approximately 80% of the strength that existed prior to injury.28 An esophageal anastomosis leak can be caused by intrinsic patient factors, inadequate tissue perfusion, the negative pressure within the thoracic cavity, or mechanical factors.25 Patient factors that can negatively affect the healing process include preoperative malnutrition, obesity, heart failure, hypertension, diabetes, renal insufficiency, and tobacco use.20 Calcification of the aorta and other arteries that supply the gastric conduit is an emerging risk factor because it may indicate low blood supply to the organ, which can interfere with the healing process. 20,22 The thoracic cavity has a negative pressure that can draw gastric fluids through the anastomosis, which can cause infection and interfere with healing. 29 Minimizing anastomotic tension is also an important factor in esophageal anastomosis creation.3 Tension may create a gap in the suture or staple line that prevents the lumen from properly sealing.3 Staple line disruption including intersecting staple lines and incorrectly fired staples may increase the risk of a leak at the anastomosis site as well.3 History and Physical An anastomotic leak can present within days, weeks, or months following an esophagectomy, and symptoms can vary from no clinical symptoms to severe and sudden sepsis.19 There are nonspecific and specific presentation of clinical symptoms.19 Tachycardia, arrythmia, leukocytosis and respiratory failure are nonspecific because they can be related to conditions such as pneumonia or infection. 19 Additionally, arrhythmia, subcutaneous emphysema, chest pain, pneumothorax and pleural effusion are frequent nonspecific symptoms of sepsis due to mediastinitis or pneumonia. 19 Specific symptoms 18 include redness and swelling to the incisions or a change in the nature of drain contents. 19 Anastomotic leak severity is classified into four grades.19 Grade 1 is diagnosed by radiology or endoscopy and has no clinical signs. 19 Grade 2 shows an inflammatory lesion and minor clinical symptoms. 19 Grade 3 shows severe disruption and sepsis with major clinical findings.19 Grade 4 is conduit necrosis diagnosed with endoscopy. 19 Evaluation Once a patient is exhibiting symptoms, diagnosis can be made by utilizing laboratory markers, endoscopy, or imaging such as contrast esophagram or computed tomography, usually in conjunction with one another. Inflammatory laboratory markers that are most commonly used include white blood cells, C-reactive protein (CRP) and lactate.19,30 These may be elevated in the presence of an anastomotic leak. An upper gastrointestinal endoscopy (or EGD) is a procedure where a flexible tube with a camera called an endoscope is inserted through the mouth to examine the esophagus.31 This test can be helpful in determining the presence and location of a leak as well as the condition of the esophageal conduit.32 Immediate treatment can also be performed if a leak is observed.32 Esophagram and computed tomography are two imaging tests that are often performed to evaluate for an anastomotic leak. An esophagram is a dynamic x-ray exam that uses fluoroscopy to observe contrast material that is taken by mouth, as it passes through the esophagus.33 The patient is placed in various positions as they are drinking to observe if there is any contrast that extends beyond the lumen of the esophagus indicating an anastomotic leak.34 Computed tomography is a radiology test that uses cross-sectional imaging to show various pathology.35 CT esophagography uses oral contrast to look for extraluminal contrast to suggest an anastomotic leak. 35 Even without contrast, CT has the 19 ability to show extraluminal gas locules located adjacent to the esophagus, pneumomediastinum, pneumothorax, pleural effusion, and abscess, which can all correspond to an anastomotic leak.36 Treatment / Management Options Management strategies for anastomotic leaks depend on the severity of the leak. Conservative management can be utilized to treat leaks that have little to no symptoms or small late leaks of the esophagus.20 This may entail broad-spectrum antibiotic therapy, NPO status with feeding tube placement for nutrition, drain placement, or a combination of these options.20 There are various ways to treat anastomotic leaks with endoscopy that do not require full surgical intervention. Placement of self-expanding metallic stents (SEMS) which cover the esophageal lumen to allow healing are an option for patients that are symptomatic and/or experiencing necrosis. 20 Stents require the placement of a drain to remove fluid outside the esophagus; the drain and stent are usually left in place for 4-8 weeks.20 Endoscopic over-the-scope clips (OTSC) can be used to close small leaks of the esophagus when there is minimal inflammation and healthy mucosa by performing fullthickness closure of the defect.20 Endoscopic vacuum therapy (EVAC) can be used to promote tissue healing and improved circulation by placing a sponge in or outside of the esophageal lumen near the leak.20 A nasogastric tube is then placed near the sponge where vacuum negative pressure can be applied to drain secretions and bacterial drainage. The sponge is exchanged every 3-7 days, and the mean healing time is around 20 12-36 days.20 Additionally, there are different types of sealants and glues that can be applied after sponge removal to help seal residual leaks.20 Surgery is an option that is usually used to treat early leaks that result from a technical failure.20 Leaks that have failed conservative or endoscopic treatment, leakages in severely septic patients, non-contained mediastinitis, empyema, and necrosis are also treated using surgical methods.20 A thorascopic approach can be used for debridement, suturing, and mediastinal drainage in early cases. 20 When empyema or sepsis are involved, open exploration is mandatory. 20 If there is necrosis and local ischemia, a reanastomosis should be performed.20 Sometimes this is done with a pedicle flap to reinforce the anastomosis.20 In rare cases, a temporary cervical esophagostomy (spit fistula) is created to allow for an anastomosis takedown and full recovery to take place, after which time, the gastrointestinal continuity can be restored with colon or jejunum. 20 Complications Anastomotic leak is a feared complication of esophagectomy, which can even be more serious than leaks of other parts of the gastrointestinal tract due to its location in the thoracic cavity.29 Esophageal anastomotic leaks often involve pleural contamination, infection, and obstructions that affect negative intrathoracic pressure. 29 The negative pressure causes gastric fluid to be easily drawn through the anastomosis creating leaks, and this can lead to respiratory problems and unstable hemodynamics.29 Anastomotic leaks of the esophagus also have the potential to cause sepsis and multiorgan system 21 failure.21 All of these complications have the potential to lead to prolonged hospitalization, decreased quality of life, and reduced life expectancy. 21 Summary An anastomotic leak is a complication of esophagectomy that occurs at very high rates. Esophageal resection is most often performed as a treatment for esophageal cancer, which has been rapidly increasing in recent decades.27 Because there are a multitude of factors that can increase the incidence of an anastomotic leak, a clear or specific cause can rarely be established. Preoperative patient factors and comorbidities, surgical techniques, and postoperative protocols can all influence how an anastomosis will heal. An esophageal anastomotic leak can be caused by intrinsic patient factors, inadequate tissue perfusion, the negative pressure within the thoracic cavity, or mechanical factors.25 An anastomotic leak can present within days, weeks, or months following an esophagectomy, and symptoms can vary from no clinical symptoms to severe and sudden sepsis.19 Once a patient is exhibiting symptoms, diagnosis can be made by utilizing laboratory markers, endoscopy, or imaging such as contrast esophagram or computed tomography. Management strategies for anastomotic leaks depend on the severity of the leak. Anastomotic leaks can be treated conservatively, using various endoscopy techniques, or with a surgical approach. An anastomotic leak is a feared complication of esophagectomy, usually more serious than leaks of other parts of the gastrointestinal tract due to its location in the thoracic cavity. 29 22 Chapter 3: Literature Reviews Documentation The Weber State University Library and Google Scholar were used to search for topics pertaining to improving outcomes in patients with anastomotic leaks following esophagectomy. General Literature Review The purpose of the general literature review is to understand anastomotic leaks including patient-related factors, current surgical techniques, methods for detecting suspected anastomotic leaks, as well as the types of treatments currently in use. Patient-Related Factors There are patient-related factors that influence the likelihood that a person will develop an anastomotic leak.,37 Specifically, there are factors that can be adjusted to improve patient outcomes. These factors include nutrition, smoking and alcohol use, chemotherapy, blood transfusions, hypotension and the use of pressor agents, hypertension, peripheral vascular disease, cardiac arrhythmias, reduced cardiac contractility, and diabetes mellitus.5 Nutrition Of all cancers, esophageal has the highest median weight loss prior to diagnosis.7 Complications are more likely to occur in patients that are nutritionally depleted, which may affect up to 80% of esophageal cancer patients.7 Malnourished patients should receive 5-7 days of immune-modifying nutritional support to help aid in the reduction of infection rates and anastomotic leaks.5,7 Supplements should be high in protein and include glutamine, arginine, n-3 fatty acids, and ribonucleic acid which are immune- 23 enhancing.5,7 Some studies have shown benefits of total parental nutrition (TPN) administered to postoperative patients who are unable to tolerate oral nutrition but studies have not been performed using this preoperatively. 5 Early oral feedings have increased positive outcomes compared with parental nutrition.7 Feeding tubes may also be employed when complications make the patient unable to eat, or if there is risk of vomiting or aspiration pneumonia.7 Smoking and Alcohol Use Daily smokers have an increased risk of pulmonary and wound complications, and alcohol abusers similarly have increased hemorrhagic, wound, and cardiopulmonary risks.7 Smoking has a four-fold associated risk of anastomotic leak compared with nonsmokers.5 At least 4-8 weeks of preoperative smoking cessation as well as 4 weeks postop is required to reduce complications in smokers.5 Similarly, a 4 week abstinence from alcohol decreases complication rates.8 Chemotherapy and Radiation Chemotherapy drugs can negatively affect wound healing by attenuating the function of the immune system.3 Most studies performed on the use of chemotherapy focus on colorectal anastomoses.5 Some studies suggest that there is an increase in anastomotic leak following chemotherapy, but others do not show this correlation.5 Studies have not shown an increase in anastomotic leakage in esophageal surgery.5 New forms of chemotherapy, however, including vascular endothelial growth factor inhibitors (bevacizumab) have been shown to increase late anastomotic leaks.5 Current recommendations are to hold these medications a minimum of 28 days prior to and following surgery.5 The results of studies looking at the use of neoadjuvant 24 chemoradiation on the occurrence of anastomotic leakage are inconclusive.13 Some studies suggest there is no correlation, but others suggest that higher doses of radiation to a cervical anastomosis can increase the risk of anastomotic leak. 13 Hypotension Conventionally, routine admission to the ICU, with patients sedated, intubated, and ventilated after esophagectomy can have increased rates of hypotension.7 Interoperative and postoperative use of vasopressors and fluid replacement to treat hypotension has shown to increase risk of anastomotic leak by 3 to 4 times.5 The longer the exposure to these medications, the higher the risk, so these should be avoided unless absolutely necessary.5 Thoracic epidurals and minimally invasive surgical techniques can help with pain management and allow for immediate extubation leading to both better patient outcomes and less economic costs. 7 However, there is also a possibility that intraoperative epidural catheters may significantly influence gastric blood flow during hypotensive episodes under certain conditions.38 Blood Transfusions Blood transfusions have been shown to be a risk factor for both hospital acquired infections and carry a very high association with anastomotic leak.5 Intraoperative blood loss is also a risk factor for the development of anastomotic leak. These may be more of a reflection of intraoperative and postoperative complications.5 However data is increasingly showing that blood transfusion alone can be a risk factor for hospital acquired infections.5 25 Comorbidities Comorbidities such as diabetes mellitus, hypertension, peripheral arterial disease, and heart disorders such as cardiac arrhythmias, and reduced cardiac contractility must be thoroughly reviewed and optimized prior to surgery as these can contribute to higher risks of anastomotic leak.37 Defective glucose control with diabetes, for example, leads to vascular damage and decreased blood flow as well as toxic glucose-derived products accumulating within the cells.3 Hypertension is a risk factor in developing postoperative atrial fibrillation which is also a risk of anastomotic leak. 39 Cardiac arrhythmias, specifically atrial fibrillation, is a complication of esophagectomy that has a significantly higher risk for postoperative events, including anastomotic leak. 39 This may be due to an increase in hemodynamic instability and reduced blood flow to the anastomosis. 39 The incidence of postoperative atrial fibrillation is about 16 percent. 39 Hypertension and coronary artery disease were shown to be risk factors for atrial fibrillation. 39 Surgical Techniques There are many different approaches to esophagectomies due to differing anastomosis location, the choice of conduit, as well as the route of reconstruction. 6 According to a worldwide survey from 2016 of surgeons who perform esophagectomies for tumors of the esophagus, the minimally invasive transthoracic approach was preferred by 43% of respondents.40 This was followed by the open transthoracic approach (38%), the open transhiatal approach (15%) and the minimally invasive transhiatal approach (4%).40 The survey found that there was a three-fold increase in surgeons who preferred the minimally invasive technique compared to a survey done in 2007. 40 26 Choice of Conduit The most used organ to substitute for the esophagus after esophagectomy is the stomach, but the colon and the jejunum can also be used. 7 The stomach is relatively easy to mobilize to reach even the neck, and only one anastomosis is required. 7 However, disadvantages to using the stomach include sensitive vascularization and potential for damage during preoperative radiation of distal esophageal tumors, both of which can impact healing at the anastomosis site.7 There is also tendency for patients to experience chronic reflux of acid and bile.7 The stomach cannot be used if it was previously resected or if the tumor involves the proximal stomach. 7 Colon has a long length, great blood supply, and more resistance to acids, but a longer operative time is required, and three anastomoses are needed.7 Evaluation of the colon with imaging or endoscopy with the addition of bowel prep are also necessary prior to surgery.7 Jejunal conduits have a low leakage rate but require technically complex anastomoses to reach the upper thorax and neck.7 Transthoracic (Ivor Lewis) Esophagectomy A transthoracic esophagectomy, also known as an Ivor Lewis esophagectomy is used for patients with tumors in the middle or lower third of the esophagus. 41,42 A laparotomy (open) or minimally invasive technique is performed to mobilize the stomach.41 A pyloromyotomy is added, in which a cut is made in the pyloric muscle to allow for easier gastric emptying.41 Lymph node dissection is performed, and a jejunostomy tube is also placed for postoperative feeding.43 A right chest approach is then used to dissect lymph nodes and remove the diseased esophagus following with reconstruction using the stomach.41,42 The stomach and gastroesophageal junction are 27 brought through the chest cavity and a stapler is used to resect the stomach in a line from the proximal greater curvature to the lesser curvature.41 Additionally, transection of the esophagus is performed at least 10 cm above the proximal margin of the tumor. 41 The esophagus is then anastomosed to the anterior wall of the gastric tube near the greater curvature.41 Transthoracic 3 incision (McKeown) Esophagectomy A McKeown esophagectomy is indicated for carcinoma of the upper, middle or lower third of the esophagus.44 The first part of the McKeown esophagectomy can be performed open or thorascopically and consists of thoracic esophageal mobilization with lymph node dissection.44 This is followed by open or laparoscopic abdominal exploration with stomach mobilization and lymph node dissection.44 A left cervical (neck) incision created for the anastomosis.44 Reconstruction is then performed by pulling the gastric tube up to create a cervical anastomosis.44 Transhiatal (Orringer) Esophagectomy A transhiatal esophagectomy begins by entering the peritoneal cavity through a midline incision.45 The stomach is mobilized, and lymph node dissection is performed. 45 A pyloromyotomy is carried out to allow for easier gastric emptying followed by a jejunostomy tube being placed beyond the ligament of Treitz for postoperative feeding.45 The diaphragmatic hiatus is then dilated until a hand can be inserted into the posterior mediastinum.45 Dissection of the distal esophagus and lymph nodes is then executed.45 Mobilization of the esophagus is carried out to the level of the carina.45 With attention turning towards the neck, an incision is created paralleling the anterior border of the sternocleidomastoid muscle, dissecting down until the esophagus is reached. 45 Working 28 both from the diaphragmatic hiatus and the cervical incision, the rest of the esophagus is mobilized.45 The stomach is then manipulated through the mediastinum to the base of the neck where a cervical esophagogastric anastomosis is performed.45 The diaphragmatic hiatus is then narrowed and both incisions are closed. 45 Diagnosis of Anastomotic Leaks Diagnosis of an anastomotic leak can be made from clinical signs, drain analysis, laboratory markers, imaging tests such as contrast esophagram or computed tomography with or without oral or IV contrast, or with endoscopy. Clinical Signs and Drain Analysis Early recognition of anastomotic leak following esophagectomy can be difficult from a clinical standpoint due to the various presentations that can be similar to normal postsurgical inflammatory response and infection. 19 Signs vary from clinically silent to extremely septic.19 Clinical manifestations may include fever, tachycardia, arrhythmia (usually atrial fibrillation), respiratory failure, and unexplained leukocytosis.19 In cases with a cervical anastomotic leak, redness and swelling may be seen along the incision.19 Surgical drains may also help with diagnosis.19 Drainage of bile, enteric contents, saliva, or air into the drain may indicate an anastomotic leak.19 Bedside swallow tests using methylene blue dye can be indicative of a leak if dye appears in the drain after it is ingested.19 Laboratory Markers Laboratory studies can help diagnose an anastomotic leak. Inflammatory serological markers such as white blood cells, C-reactive protein, and lactate, may be elevated in the presence of a leak.19,30 29 WBC or white blood count measures the number of leukocytes circulating in the blood.46 Leukocytosis, or a high number of white blood cells, can be indicative of an infection developing from an anastomotic leak.30 WBC numbers elevate and peak on the first or second postoperative day and then trend downward.30 In patients with an anastomotic leak these levels may be significantly higher in the days following. 30 CRP is a protein produced by hepatocytes that respond to inflammatory cytokines.30 These levels normally increase after surgery and peak after 48 hours under normal circumstances; however, they may continue to be elevated in the presence of an anastomotic leak.30 Lactate is a product of cell metabolism that is normally at very low levels in the blood.47 It is produced in excess by cells (usually muscle or red blood cells) when there is insufficient oxygen, or when the primary way of producing energy is disrupted.47 It can be a useful tool to identifying patients with inflammation and sepsis.48 High serum lactate levels in days one to three following esophagectomy have shown to be associated with an anastomotic leak.49 Contrast Esophagram An esophagram is an imaging procedure in which a patient takes contrast by mouth and it is observed in real time as it passes through the esophagus using radiographic fluoroscopy equipment.33 An esophagram can be performed to evaluate the function and lumen of the esophagus for diagnosis of pathology and for preoperative staging purposes.33 When an anastomotic leak is suspected, the radiologist or radiologist assistant positions the patient in various upright and recumbent positions during the exam watching specifically for the presence of extraluminal contrast.34 Operative notes can 30 help determine the location of a potential leak. There are three areas where an anastomotic leak may occur depending on the surgery performed: the esophagogastric (or enteric) anastomosis, the gastric or enteric staple line, or the pylorus. 34 Postoperative esophageal function can also be assessed simultaneously during the exam checking for pathology such as strictures or esophageal emptying.50 Water-soluble non-ionic contrast is used in instances where esophageal perforation is suspected because barium is inert and will not be absorbed within the mediastinum and peritoneal structures.33 Computed Tomography CT esophagography is an imaging test that uses cross-sectional imaging and oral contrast to detect anastomotic leaks of the esophagus. 35 CT can show extraluminal contrast, extraluminal gas locules adjacent to the esophagus, pneumomediastinum, pneumothorax, pleural effusion, and abscess which can all be indicative of an anastomotic leak.36 Contrast can be taken by mouth, or in instances where a patient cannot drink, it can be injected via a nasogastric tube that is positioned proximal to the anastomoses.35 Intravenous contrast can be given in addition to oral contrast, and this can help diagnose pathological conditions such as abscess, pulmonary embolism, or pneumonia when the patient is experiencing acute chest pain. 35 The first part of the study is a frontal and lateral scout CT from the angle of the mandible to the iliac crest.35 This determines the scan coverage, but it can also demonstrate the location of NG tubes (which can be adjusted prior to contrast administration), surgical sutures, or other radiopaque material such as calcifications to later compare with postcontrast images. 35 If the patient can drink, they will then sit upright and drink 4 oz of water-soluble non-ionic contrast.35 Some institutions may also thicken the contrast.35 They will then be asked to 31 lay back down and consume an additional 4 oz of contrast in the supine position.35 If intravenous contrast is also requested this will be administered while the patient is drinking in the supine position.35 The patient is then scanned. If an anterior leak is suspected, the radiologist may then determine if prone imaging is needed in addition to the supine images.35 Endoscopy An upper gastrointestinal endoscopy (or EGD) is a procedure where a flexible tube with a camera called an endoscope is inserted through the mouth to examine the esophagus.31 However, especially in the early preoperative phase, minimal insufflation should be used to not to damage the anastomosis. 32 This test can be helpful in determining the presence and location of a leak as well as the condition of the esophageal conduit.32 Additionally, immediate treatment of an anastomotic leak can be performed. 32 Treatments Basic management strategies include closure or coverage of the anastomotic leak, leak containment, and drainage of fluid collections. 20 The type of treatment depends on the localization and size of the leak, symptom severity, presence of ischemia or necrosis of the conduit, and timing after surgery.20 Treatment varies between conservative management, endoscopy, or surgery.20 Conservative Methods Conservative measures can be used to treat asymptomatic (or minimally symptomatic), late leaks of the cervical, or intrathoracic esophagus.20 Cervical anastomotic leaks are usually treated by NPO status combined with jejunostomy tube feeds for 1-3 weeks.20 For minimally symptomatic intrathoracic leaks, surveillance, and 32 jejunal feeding, with possibility of a mediastinal drain placement can be used. 20 Broadspectrum antibiotic therapy is also used to treat infection.20 Endoscopy There are several techniques that can be performed with endoscopy when a patient is symptomatic and/or experiencing conduit ischemia.20 Self-expanding metallic stents (SEMS) are a type of prothesis that is positioned in the esophageal lumen that covers the defect to allow for tissue healing. 20 A drain must be placed with this technique to allow fluid outside of the lumen to be removed.20 Median stenting time is around 4-8 weeks, and risks include stent migration, tissue overgrowth and esophageal injury such as ulcers, erosions, bleeding, perforation, fistula, and reflux.20 Endoscopic vacuum therapy (EVAC) places an open-pored polyurethane sponge in the abscess cavity or esophageal lumen of an intrathoracic anastomotic leak.20 A nasogastric tube is placed near the sponge and vacuum drainage with negative pressure is applied to allow for continuous drainage of secretions and bacterial contamination.20 This promotes granulation tissue proliferation and improves microcirculation. 20 The sponge is changed every 3-7 days, and the process is terminated when stable granulation tissue covers a self-cleaning inner wound.20 Mean healing times range from 12-36 days and complications include possible stricture formation, bleeding, rupture of the aorta from erosion, bronchoesophageal fistula, mucosal tear with sponge removal, and sponge dislocation.20 Endoscopic over-the-scope-clips (OTSC) are a possible treatment for small endoscopic leaks.20 This provides a full-thickness durable closure of the wall of the esophagus.20 They are indicated in cases of acute anastomotic leak for tissues with 33 minimal inflammation and reasonably healthy mucosal edges.20 Complications are rare and include detached clip, contralateral esophageal ulceration, and esophageal perforation.20 Sealant with cyanoacrylates and fibrin glues can be used to treat small anastomotic leaks or residual leaks after the use of EVAC.20 Complete closure usually requires multiple applications and effectiveness can be improved with the combined use of a vicryl plug or clip in conjunction with the sealant. 20 Surgery Surgical treatment is indicated for early leakages since these are usually attributed to technical failure.20 Leakages that have failed conservative or endoscopic treatment, leakages in severely septic patients, non-contained mediastinitis, empyema, and necrosis of the conduit are also treated with surgery.20 There are several ways that surgery can used. A thorascopic approach can be used for debridement, suturing, and mediastinal drainage in early cases.20 When empyema or sepsis are involved, open exploration is mandatory.20 If there is necrosis and local ischemia, a re-anastomosis can be performed.20 Sometimes this is done with a pedicle flap to reinforce the anastomosis. 20 In rare cases, a temporary cervical esophagostomy (spit fistula) is created to allow for an anastomosis takedown and full recovery to take place.20 After which time the gastrointestinal continuity can be restored with colon or jejunum.20 Summary This general literature review explained patient-related factors, current surgical techniques, methods for detecting suspected anastomotic leaks, as well as the types of treatments currently in use. 34 Case Study Literature Review The case study literature review examines a variety of research studies mostly in the retrospective form related to newer techniques, detection methods, and treatments for anastomotic leaks and esophagectomy. Preoperative Patient Selection and Preconditioning Arterial Calcification Detection There is evidence that calcification in the thoracic aorta, celiac axis, or the right post-celiac arteries when seen on CT scans, can contribute to the development of anastomotic leaks.22 Most patients undergoing esophagectomy will have CT scans performed for staging purposes, so examination of arterial calcification is easy to incorporate into practice.22 Arterial calcification and celiac trunk stenosis seem to be reliable risk factors for predicting anastomotic leakage.22 Understanding a patient’s risk may allow for modification of management of high-risk patients.22 Ischemic Gastric Preconditioning Poor perfusion of the gastric conduit can increase the incidence of anastomotic leak.51 Ischemic gastric preconditioning is performed preoperatively to partially destroy the larger gastric vessels to then improve gastric perfusion by triggering new vessel formation in the mucosal and serosal layers.51 This can be performed endovascularly in interventional radiology or by a surgical approach.52 Barberio et al performed a porcine study on 16 pigs and at day 21 gastric perfusion was assessed. The study suggests that sole embolization of the left gastric artery or laparoscopic division of the short gastric arteries can improve gastric fundus perfusion. 51 35 Surgical Techniques Choice of Conduit The tissue that is chosen to replace the esophagus during an esophagectomy can vary.6 The stomach is accepted as the first choice, and this is known as the gastric pull-up method.6 If the stomach is not a suitable choice, the jejunum (jejunal flap) or colon (colon interposition) may be used.6 Hung et al performed a meta-analysis of nine studies involving 1613 patients comparing different reconstruction methods for esophagectomy.6 They found that the jejunal flap had advantages over the gastric pull-up concerning anastomotic leakage and that colon interposition had a high probability for anastomotic leak.6 Surgical Technique Leak Rates The rate of anastomotic leak is highest following transhiatal esophagectomy, followed by McKeown esophagectomy, with Ivor Lewis esophagectomies having the lowest rate of anastomotic leak.22 Verstegen et al performed a retrospective study comparing patient outcomes following different esophagectomies.53 They found anastomotic leak rates were 19.7% after transhiatal esophagectomy, 16.9% after Ivor Lewis esophagectomy and 22.2% after McKeown esophagectomy.53 However, this study found that that anastomotic leak complications following the transthoracic approach may have lower mortality, re-operation, and ICU readmission rates followed by McKeown and Ivor Lewis.53 Cervical anastomotic leak rates are higher, but they tend to have less severe consequences compared to intrathoracic leaks.53 The higher leak rates to cervical anastomosis may be caused by the need for a longer gastric conduit with need to position the anastomosis near the less-vascular fundus or by the increased tension and/or 36 compression between the thorax and neck.20 However, cervical anastomoses can be technically less challenging, and if an anastomotic leak occurs, it can be managed more easily.54 Wang et al performed a review and meta-analysis of studies comparing anastomotic leak rates between McKeown and Ivor Lewis esophagectomies. 23 They found 23 publications that reported the rate of anastomotic leakage after surgery.23 This included 3,922 patients.23 The occurrence rate of anastomotic leakage was 14.7% in minimally invasive McKeown esophagectomy, and 5.5% in minimally invasive Ivor Lewis esophagectomy.23 Three of these studies, which included 1,541 patients, studied the incidence of anastomotic leakage that required surgery. 23 This study indicated that again, anastomotic leakage that required surgery was significantly higher in patients who underwent minimally invasive McKeown esophagectomy. 23 Robotic Esophagectomy Manigrasso et al performed a meta-analysis of clinical outcomes following robotic esophagectomy.55 Robotic-Assisted Minimally Invasive Esophagectomy (RAMIE) can improve the view of thoracic structures and increase precision compared with the minimally invasive method.55 Their results also showed that the robotic approach is far superior to an open approach possibly due to the magnification of images and finer dissection movements.55 The only disadvantage found was the length of operation which was slightly longer with robot assisted.55 In terms of the risk of anastomotic leak, in a subgroup analysis between fully robotic vs. fully laparoscopic procedures (McKeown and Ivor Lewis esophagectomies) there were no significant differences in the rate of anastomotic leakage between either surgery.55 There was also no 37 statistical difference in anastomotic leak rates between robotic assisted or open procedures.55 Omentoplasty An omentoplasty is a technique where the greater omentum is wrapped around a gastrointestinal anastomosis.56 The omentum can induce neovascularization and localize inflammatory processes to potentially decrease the incidence and severity of an anastomotic leak.56 Chen et al performed a meta-analysis of randomized control trials comparing omentoplasty with an uncovered anastomosis for the prevention of anastomotic leaks post esophagectomy.56 The study found that use of pedicled omentum to oversew the anastomosis may decrease the incidence of anastomotic leakage and reduce the duration of hospital stay. 56 There was also no significant differences in the anastomotic stricture rate between the omentoplasty and non-omentoplasty groups.56 Tuo et al similarly performed a meta-analysis of outcomes of omentoplasty on esophageal anastomoses.57 They also concluded that an omentoplasty is safe and feasible, and improves outcomes particularly for cervical anastomoses. 57 Stapled or Handsewn Anastomosis Järvinen et al performed a meta-analysis of 19 studies to determine whether handsewn or stapled anastomoses had higher rates of anastomotic leaks. 58 The study found that handsewn anastomoses had a higher rate of leak and stricture especially with cervical anastomoses.58 There was no difference favoring techniques in the studies with only intrathoracic anastomoses.58 There was discrepancy when subjected to sensitivity analysis so a conclusion could not be made as to what technique is preferred.58 Hofmann et al performed a retrospective review of 119 patients to discover whether different sizes 38 of circular endoscopic stapling devices would impact the rate of anastomotic leak following minimally invasive Ivor Lewis esophagectomy. 59 They study found that the larger 29 mm diameter circular stapler had a significantly lower rate of leak than a 25 mm diameter stapler.59 Detection of Anastomotic Leaks Contrast Esophagram, Computed Tomography, and Endoscopy Contrast esophagram and computed tomography are both imaging modalities that can be used to detect an anastomotic leak, but localization is often challenging. 9 Palacio et al performed a retrospective study to compare both modalities in detecting anastomotic leaks.9 382 patients underwent an esophagectomy between September 1, 2005 and August 31, 2009 and 125 patients developed symptoms of an anastomotic leak.9 121 patients were imaged with 17 having a CT, 36 had an esophagram, and 68 patients underwent both studies within the first month after surgery. 9 The study found that in the group of 68 patients where both CT and esophagram studies were performed, 13 patients had false-negative results on the CT study whereas the esophagram studies only had 4 false negative results.9 The study did not state when these exams took place so some may have been performed before a leak was evident. However, when timing was accounted for, a comparison of patients with both exams performed within 3 days of each other had improved results (false negatives of 3 for CT and 2 for esophagram).9 They also found that CT was more accurate when performed at least 14 after surgery.9 CT was also more likely to have false-positive results (3 on CT and 1 on esophagram).9 40% of leaks on CT are diagnosed on the basis of extraluminal air, fluid, or contrast in the mediastinum. 9 However, air or fluid in the mediastinum can be a normal finding in postoperative 39 patients without an anastomotic leak.9 They did state that all patients with conduit leaks requiring intervention were diagnosed with imaging.9 They also discussed that irregularity of the anastomosis site may create false-positive studies on esophagram, especially when a side-to-side anastomosis is performed.9 This study concluded that esophagrams are more sensitive than CT in detecting anastomotic leaks but CT is useful in diagnosing clinically significant leaks and additional co-existing or unrelated findings such as pleural effusion, chylothorax, pneumonia, or pulmonary embolism.9 Hu et al performed a retrospective study to find the diagnostic value of contrast esophagrams.8 The study looked at 846 patients that underwent esophagectomy from 2013 to 2014.8 57 patients went on to develop an anastomotic leak (36 cervical and 21 in the intrathoracic region).8 In the cervical anastomotic leak patients, 13 were diagnosed by clinical symptoms, 23 underwent routine contrast esophagram and 7 (30.4%) were truepositive, 11 (47.8%) were false-negative, and five (21.8%) were equivocal cases.8 With the intrathoracic anastomotic leak patients, four (19%) were diagnosed by clinical symptoms, 16 (76.2%) were true positives, and one (4.8%) was a false negative. 8 They found that there is a low sensitivity in detecting cervical anastomotic leaks with esophagram, so this exam is not advised.8 For intrathoracic anastomoses, esophagram is effective in detecting anastomotic leaks.8 Griffith et al. presented a case study of a patient with a duodenal adenocarcinoma who underwent a surgical resection with drain placement. 60 On postoperative day 3, the patient was experiencing worsening abdominal pain and continued serosanguinous output from the surgical drain, so an Upper GI series was ordered.60 During the exam, contrast was noted adjacent to the anastomosis, but it was unclear whether this represented a leak 40 or postoperative changes.60 90 minutes after the fluoroscopy study, a CT abdomen/pelvis without contrast was performed.60 There was no obvious sign of a leak on the scan, but contents of the drain appeared hyper-attenuating suggesting an anastomotic leak.60 This case study shows the utility of CT following ambiguous clinical or fluoroscopic presentation by examining drain contents.60 Schaible et al performed a blind intraindividually controlled study between January 2006 and September 2007 to compare contrast esophagram to endoscopy for identification of complications post esophagectomy. 61 Of 55 patients that underwent transthoracic subtotal esophagectomy only 35 were able to have a contrast esophagram, 20 could not be performed due to contraindications or mechanical ventilation. 61 Endoscopy was able to be performed on all 55 patients. 61 Pathologic findings were detected in 13 patients with endoscopy but only in 1 patient with esophagram. 61 Leakage of the anastomosis or the conduit was correctly detected in 7 patients by endoscopy but in only 1 patient by contrast swallow and 6 patients were additionally found to have conduit necrosis via endoscopy.61 Esophagram showed two false-positive results.61 They found that endoscopy is possible in all patients and is superior to esophagram in detecting pathological findings.61 Treatment Options Interventional Radiology Bi et al performed a retrospective study between January 2013 and February 2018 to determine the safety, feasibility, and efficacy of interventional radiology as a treatment for esophageal anastomotic leakage.12 23 patients with anastomotic leak were treated with a three-tube method with or without esophageal stent placement by interventional 41 radiology; eight patients received covered stents during this study.12 The three tubes placed included an abscess drainage tube, gastrointestinal decompression tube and jejunal feeding tube.12 Abscess drainage, anti-inflammatory treatment and nutritional support was then performed.12 All operations were technically successful with nonexistent abscesses remaining in 16 patients and markedly decreased abscesses in 7 patients. 12 Stent migration occurred in 5 patients and one patient showed migration of the abscess drainage tube.12 The study demonstrated that interventional radiology can be easily performed with no serious complications and once the fistula heals, stent removal is safe and feasible.12 Bovine Pericardial Patch Repair Hua et al performed a study of patient whom underwent bovine pericardial patch (BPP) repair of an anastomotic leak of the cervical esophagus following esophagectomy.62 BPP is mainly used in cardiovascular surgery, but it has also been applied to esophagogastric anastomoses.62 BPP is a type of membrane composed of multidirectional fibers with strengths and extensibilities that can cover vulnerable tissue and prevent exosmosis of digestive juice. 62 All patients had an end-to-side esophagogastric mechanical anastomosis with a 25-mm-diameter circular stapler.62 18 patients in study developed an anastomotic leak. 11 were treated with conservative management and the other 7 developed a persistent intractable leak.62 These 7 patients were treated with a bovine pericardial patch repair. The repair is performed under general anesthesia starting with debridement of the leakage, repair of the leak with the bovine pericardial patch, followed by drain placement.62 The repair was performed a median 45 days after esophagectomy.62 In all 7 patients, there was no recurrence of anastomotic 42 leakage after BPP repair.62 No patients had dysphasia, and no patients developed a surgical site infection.62 Sternocleidomastoid Flap Repair Nakajima et al performed a study to investigate the effectiveness of sternocleidomastoid flap repair for anastomotic leak after esophagectomy. 63 The surgery begins with debridement and excision of the fistula.63 Repair of the gastric stump is performed with interrupted absorbable sutures in a single-layer fashion.63 The SCM flap is then created using the left SCM.63 The SCM is dissected, sternal head is exposed and then dissected from the manubrium of the sternum, preserving the clavicular head of the SCM.63 The separated sternal head is then moved to patch the repaired gastric stump. Finally, a drain is inserted near the muscle flap.63 The study included 158 patients who underwent esophagectomy with a cervical anastomosis. 63 18 patients developed an anastomotic leak.63 10 healed with conservative treatment and 8 developed a refractory fistula that subsequently underwent SCM flap repair to fix the leak. 63 2 operations were performed under general anesthesia with regional and intravenous anesthesia used for the other 6.63 The SCM repair was performed at a median 50 days after esophagectomy.63 In all 8 patients, there was no recurrence of anastomotic leakage after repair.63 No patients had swallowing discomfort or problems with neck mobility, and no patients developed a surgical site infection.63 Summary The case study literature review examines a variety of research studies mostly in the retrospective form related to newer techniques, detection methods, and treatments for anastomotic leaks following esophagectomy. 43 Chapter 4: Research Method Anastomotic leaks following esophagectomy continue to occur at high rates despite advances in surgical techniques. Prompt diagnosis of anastomotic leaks and proper treatment is imperative for improving patient outcomes. The purpose of this study is to inform the reader of known patient risk factors, current surgical practices, best methods for the detection of anastomotic leaks, current treatments being employed, as well as advancements and new research on the subject. Research Method The research method being used is a literature review of articles and research studies pertaining to anastomotic leaks following esophagectomy. Materials chosen were ideally published within the last 10 years and were journal articles, textbooks, and websites. A few articles used were older than 10 years. Randomized control trials were searched but most research conducted was in the form of retrospective patient reviews. Information searched pertained to anastomotic leaks specifically postesophagectomy. Google, Google Scholar, and Academic Search Ultimate from the Weber State University Stewart Library were the search engines used to find articles. Key phrases include: “Anastomotic leak esophagectomy”, “anastomotic leak”, “anastomotic leak risk factors”, “anastomotic leak treatment”, “esophagectomy complications”, “esophageal cancer”, “Ivor Lewis esophagectomy”, “transthoracic esophagectomy”, “McKeown esophagectomy”, “transhiatal esophagectomy”, “Orringer esophagectomy”, 44 “omentoplasty”, “anastomotic leak esophagram”, “endoscopy esophageal anastomosis leak”, and “anastomotic leak computed tomography” were the topics that were searched. Population The population of patients used for this literature review included adults who underwent an esophagectomy. Sample The sample chosen for this literature review included adult patients that developed an anastomotic leak following esophagectomy. Limitations Limitations of this study include the lack of random control trials that were found in the research. Nearly all the research used were literature reviews and retrospective studies that included relatively small numbers of patients. The scope of this thesis was also a limitation. This is a very broad topic with lots of information. Delimitations Delimitations of this study included researching anastomotic leaks of only the esophagus post-esophagectomy. Other anastomotic leaks of the gastrointestinal tract were excluded. Only complications of acute anastomotic leaks were studied; other complications such as stricture, dysphasia, or other complications that can occur from esophagectomy were not discussed. Summary This thesis is a literature review of articles and research studies from the last 10 years pertaining to anastomotic leaks following esophagectomy. Anastomotic leak following esophagectomy continue to occur at high rates despite advances in surgical 45 techniques. To improve patient outcomes, the purpose of this literature review is to inform the reader about known risk factors, surgical practices, detections methods, treatments, and advancements surrounding the topic of anastomotic leaks following esophagectomy. Google scholar and Academic Search Ultimate were the main search engines used to find information. Limitations of this review included the lack of random control trials on the subject as well as the large scope of this topic. Researching only anastomotic leaks following esophagectomy was a delimitation used to narrow the scope of the literature review. 46 Chapter 5: Findings Anastomotic leak following esophagectomy continue to occur at high rates despite advances in surgical techniques. This has the potential to cause increased healthcare costs, and significant morbidity and mortality. The purpose of this literature review is to explore information surrounding the topic of anastomotic leaks following esophagectomy to help improve patient outcomes. Patient factors that increase risk of anastomotic leak are examined and surgical methods that increase risk of leak are reviewed. Once an anastomotic leak has developed, prompt diagnosis and proper treatment are very important. A discussion about different diagnostic approaches is presented as well as advancements in treatments. Results There are many patient factors that have been identified that can increase the susceptibility that a person may develop an anastomotic leak following esophagectomy. The main patient factors that have been identified are as follows: patient’s sex, obesity and malnutrition, smoking and alcohol use, blood transfusions, hypotension and the use of pressor agents, hypertension, cardiac arrhythmias, congestive heart failure, diabetes mellitus, and peripheral arterial disease.3,5,7,18,25,26 The majority of patients that go on to develop an anastomotic leak are male at a rate as high as 78%.26 A patient’s weight is also a contributing factor to potential anastomotic leak development. Patients with a BMI>30 develop a leak in up to 20.5% of cases, and similarly, patients that have a BMI<18.5 are also at higher risk of leak at about 5.4%; low BMI is especially common in patients with esophageal cancer, the main subset of patients undergoing esophagectomy.7,18,26 Smoking and alcohol use have both been 47 found to increase rates of anastomotic leak by fourfold compared nonsmokers and nondrinkers due to poor wound healing.5,18 Blood transfusions have been shown to carry a very high association with anastomotic leak. 5 Intraoperative blood loss itself is also a risk factor for the development of anastomotic leak but data is increasingly showing that blood transfusions can increase hospital acquired infections and anastomotic leaks following esophagectomy.5 Intra-operative or post-operative hypotension is a factor that has shown to increase anastomotic leak. Conventional postoperative patient management has involved ICU admission with patients intubated and sedated. 7 Sedation can lead to hypotension with subsequent IV fluid replacement and the use of vasopressors.5,7 Vasopressors may cause conduit ischemia which can increase the rate of anastomotic leak by 3 to 4 times.5,7 Thoracic epidural amnesia can offer the best analgesia allowing for immediate extubation, and epidurals can improve gastric conduit flow.7 However, some studies have found that bolusing the epidural can cause hypotension which may increase the need for vasopressors.7 Along with hypotension, hypertension can also increase the risk of anastomotic leak. Some studies have found a decrease in gastric perfusion in hypertensive patients.64 Hypertension is also a contributing factor to developing postoperative atrial fibrillation, a contributing factor for the development of anastomotic leak.39 Cardiac arrhythmias, specifically atrial fibrillation, is a complication of esophagectomy that has a significantly higher risk for postoperative events, including anastomotic leak.39 This may be due to an increase in hemodynamic instability and reduced blood flow to the anastomosis.39 The incidence of postoperative atrial fibrillation is about 16 percent.39 Hypertension and coronary artery disease were shown to be risk factors for atrial fibrillation.39 Defective glucose control in diabetes mellitus can 48 lead to vascular damage and decreased blood flow resulting from toxic glucose derived products accumulating in the cell, which can increase the risk of anastomotic leak.3 Peripheral arterial disease, specifically atherosclerotic calcification of the aorta, celiac trunk, and gastric arteries has been identified as a risk factor for anastomotic leak due to reduced gastric perfusion.3,20,22 There are different factors affecting the rates of anastomotic leak due to surgical approach, anastomosis location, and conduit choice. There are three main surgical methods used to perform an esophagectomy. The transthoracic Ivor Lewis esophagectomy is used to treat tumors of the middle or lower esophagus.41,42 It involves an abdominal laparotomy and right thoracotomy ending with a thoracic anastomosis. 41,42 The second method is the transthoracic McKeown esophagectomy which is indicated for tumors in the upper, middle or lower third of the esophagus.44 It involves an abdominal laparotomy, right thoracotomy, and left neck incision, ending with a cervical anastomosis.44 Finally, the transhiatal Orringer esophagectomy is used to treat tumors of the lower esophagus with an abdominal laparotomy and left neck incision with a subsequent cervical anastomosis.45 The rate of anastomotic leak is highest in anastomoses in the cervical esophagus following either the McKeown esophagectomy or the transhiatal Orringer approach, with the Ivor Lewis esophagectomy having the lowest rate of leak. 20,53 Cervical anastomotic leak rates are higher, but they tend to have less severe consequences compared to intrathoracic leaks.53 The higher leak rates to cervical anastomosis may be caused by the need for a longer gastric conduit with need to position the anastomosis near the lessvascular fundus of the stomach, or by the increased tension and/or compression between 49 the thorax and neck.20 However, cervical anastomoses can be technically less challenging, and if an anastomotic leak occurs, it can be managed more easily.54 Newer robot-assisted transthoracic esophagectomies are becoming more common.55 They can improve the view of the thoracic structures and increase precision compared with the minimally-invasive method, however, the surgery length tends to be a bit longer.55 In terms of anastomotic leak, studies have shown that there is no significant differences in the rate of anastomotic leakage between robotic or full laparoscopic Ivor Lewis or McKeown esophagectomies.55 The conduit that is the first choice for replacing the esophagus is the stomach, this is known as the gastric pull-up method.6 If the stomach is not a suitable choice, the jejunum (jejunal flap) or colon (colon interposition) may be used.6 Studies have found that the jejunal flap had advantages over the gastric pull-up concerning anastomotic leakage and that colon interposition had a high probability for anastomotic leak and necrosis, possibly due to bacterial contamination.6,37 The way that an anastomosis is created and reinforced can also affect anastomotic leak rates. An anastomosis can be either stapled or handsewn. Studies have shown that handsewn anastomoses have a higher rate of anastomotic leak versus a stapled anastomosis in the cervical esophagus; there was no favoring technique with intrathoracic anastomoses.58 Additionally, the size of the stapler has been shown to affect the rate of anastomotic leak. In a study examining 29mm versus 25mm diameter circular staplers, the 25mm stapler had a much higher rate of anastomotic leak.59 The anastomosis can also be reinforced with an omentoplasty, which is a technique where the greater omentum is wrapped around a gastrointestinal anastomosis.56 The omentum can induce neovascularization and localize inflammatory 50 processes to potentially decrease the incidence and severity of an anastomotic leak compared with an uncovered anastomosis.56 Prompt detection of an anastomotic leak is crucial to improving patient outcomes because it reduces the time before a patient can begin to receive treatment. Clinical signs, lab markers, esophagram, computed tomography, and endoscopy are all used to diagnose an anastomotic leak. Studies have shown that clinical manifestations such as fever, tachycardia, arrhythmia (usually atrial fibrillation), and respiratory failure can indicate an anastomotic leak but they can also indicate other postoperative complications.19 In cases with a cervical anastomotic leak, redness and swelling may be seen along the incision. 19 Drainage of bile, enteric contents, saliva, or air into a surgical drain may indicate an anastomotic leak.19 Additionally, bedside swallow tests using methylene blue dye can be indicative of a leak if dye appears in the drain after it is ingested. 19 Inflammatory serological markers that have been found to indicate an anastomotic leak include white blood cells, C-reactive protein, and lactate, which may be elevated in the presence of a leak.19,30 Contrast esophagram and computed tomography with or without contrast can be used to detect an anastomotic leak. Studies have shown that esophagrams are more sensitive than CT in detecting anastomotic leaks, especially when the tests are performed in the early days following surgery.9 However, some studies found that esophagram has a low sensitivity in detecting cervical anastomotic leaks and does a better job when detecting leaks in the thoracic esophagus.8 CT was likely to have false-positive results on early exams because many of the leaks found with CT are diagnosed on the basis of extraluminal air, fluid, or contrast in the mediastinum, however, with the exception of 51 extraluminal contrast, these can be normal findings on postoperative patients. 9 CT is useful in diagnosing clinically significant leaks and additional co-existing or unrelated findings such as pleural effusion, chylothorax, pneumonia, or pulmonary embolism. 9 There have also been cases where CT detected a leak by the presence of contrast within surgical drains.60 Endoscopy is another method that can be used with high success to diagnose anastomotic leaks. A study that compared imaging and endoscopy found that there are many instances where esophagram is contraindicated due to allergy, aspiration risk, or patient condition, however, endoscopy was possible in these patients. 61 Endoscopy is also great in determining the presence and location of a leak as well as the condition of the esophageal conduit.32 Endoscopy also has the advantage of offering treatment at the same time that a diagnosis is made.65 Basic management strategies of anastomotic leak include closure or containment of the leak and drainage of fluid collections. 20 The type of treatment depends on the localization and size of the leak, symptom severity, presence of ischemia or necrosis of the conduit, and timing after surgery.20 Treatment varies between conservative management, endoscopy, or surgery.20 Conservative measures can be used to treat asymptomatic or minimally symptomatic leaks, and late leaks of the cervical or intrathoracic esophagus.20 There are several techniques that can be performed with endoscopy when a patient is symptomatic and/or experiencing conduit ischemia. 20 Treatments include self-expanding metallic stents (SEMS), endoscopic vacuum therapy (EVAC), endoscopic over-the-scope-clips (OTSC), and fibrin glues.20 Surgical treatment is indicated for early leakages since these are usually attributed to technical failure.20 52 Leakages that have failed conservative or endoscopic treatment, leakages in severely septic patients, non-contained mediastinitis, empyema, and necrosis of the conduit are also treated with surgery.20 New techniques that are being examined to treat anastomotic leak include interventional radiology, bovine pericardial patch repair, and sternocleidomastoid flap repair. Interventional radiology has been shown to be an easy, safe, and effective method of the treatment of anastomotic leak by placing three tubes: an abscess drain, gastric compression tube, and feeding tube, with or without esophageal stent placement.12 A recent study, although small in size, showed that all operations were technically successful in treating the anastomotic leak with only minor complications such as stent migration.12 Bovine pericardial patch repair is another treatment that is mainly used in cardiovascular surgery, but is also being used as an option to treat intractable anastomotic leaks.62 The BPP membrane is applied to the site following debridement and repair of the anastomosis, followed by drain placement. 62 In all patients in the small study that was researched, there was no recurrence of anastomotic leak. 62 Sternocleidomastoid flap repair is a treatment of cervical anastomosis leaks that have failed conservative treatment.63 The repair involves wrapping the anastomosis leak with sternocleidomastoid muscle and placing a drain nearby to allow drainage. 63 The study size was also small, but no patients experienced recurrence of the anastomotic leak. 63 Evaluation of Findings Anastomotic leak following esophagectomy is a complex problem that can cause significant morbidity and mortality. There are patient factors that have been identified that increase the incidence of anastomotic leak. Careful attention to patient selection is 53 imperative and there is a necessity to correct modifiable risks that are identified prior to esophageal resection to improve surgical outcomes. Patient monitoring is important after surgery because clinical signs of anastomotic leak can be subtle. Laboratory testing can help confirm the suspicion of a leak and diagnostic imaging and endoscopy should be performed in a timely manner if there is any notion of an anastomotic leak to expedite potential treatments. If the suspicion of a leak is high early after surgery, contrast esophagram is a good option and has a high sensitivity for detecting intrathoracic anastomotic leaks, specifically. If the results are unclear or there are other complications that are suspected, computed tomography is a great modality for identifying residual extraluminal contrast, mediastinal air, or other postsurgical complications. Endoscopy is also a great diagnostic tool that is especially useful in patients that have contraindications to esophagram. Detection of small anastomotic leaks can be very difficult and there are few large-scale studies that have compared detection methods. The techniques of imaging professionals and endoscopists can affect the sensitivity of anastomotic leak detection. Knowledge of the surgery performed is imperative because it will reveal where the anastomosis, and any potential leak may be located. There are many treatment options available to treat anastomotic leaks, but this also requires careful patient monitoring and management. Current clinical and surgical research is centered around areas of prevention and early diagnosis but experimentation is risky due to the severe nature of the potential complications.3 Summary Anastomotic leak following esophagectomy continue to occur at high rates despite advances in surgical techniques. This has the potential to cause increased 54 healthcare costs, and significant morbidity and mortality. This literature review explores information surrounding the topic of anastomotic leaks following esophagectomy to help improve patient outcomes. Patient factors that increase risk of anastomotic leak are examined and surgical methods that increase risk of leak are reviewed. Once an anastomotic leak has developed, prompt diagnosis and proper treatment are very important. A discussion about different diagnostic approaches is presented as well as advancements in treatments. 55 Chapter 6: Implications, Recommendations, and Conclusions A leak at the anastomosis site after esophagectomy is a risk, that despite advances in surgical and management techniques, continues to have the potential to cause significant morbidity and mortality.4 Complications from anastomotic leaks often require the expertise of multiple specialties to manage the problem. The purpose of this literature review is to provide information about patient factors, surgical techniques, diagnostic tools, and treatments to reduce the incidence of anastomotic leaks post esophagectomy and improve outcomes in patients that develop this condition. This information was researched by utilizing google scholar and the Stewart Library at Weber State University by selecting journal articles, textbooks, and websites that were published within the last 10 years. Limitations to this research involved the large scope of the topic and the lack of random control trials that were found. Most of the research on the topic was in the form of retrospective reviews. Patient factors that increase the risk of anastomotic leak are identified and solutions are shared as to how these issues can be modified. Surgical techniques that lead to better anastomotic leak outcomes are mentioned. Diagnostic imaging recommendations are discussed, and treatments to anastomotic leak are reviewed. Implications Anastomotic leak following esophagectomy is a multifaceted problem requiring careful attention to patient selection, with a necessity to correct modifiable risks that are identified prior to surgery to reduce complications.5 Surgical techniques continue to improve especially with laparoscopic and robot-assisted surgeries becoming more commonplace.55 However, more clinical trials would be helpful to determine guidelines 56 for best surgical practices. There is also a lack of consensus about the best methods for detection of anastomotic leak. Esophagrams can be sensitive for the detection of anastomotic leaks due to the dynamic nature of the exam, but it is very dependent on the skill of the operator.34 Similarly, endoscopy is also reliant on the skill of the endoscopist.66 Computed tomography is also a great diagnostic modality, but timing can be important to obtaining accurate information about the anastomosis. 9 Anastomotic leaks have high morbidity and mortality because they are difficult to treat. This is an area that needs continued research. Endoscopy techniques such as SEMS and EVAC therapy are great options but there needs to be more clinical research in this area of treatment as well as in interventional radiology.25 Recommendations It is hard to predict which patients may develop an anastomotic leak following an esophagectomy. There are certain patient factors shown through retrospective research that correlate to an increased risk of anastomotic leak. Many of the risks have the potential to be modifiable prior to surgery, especially in elective cases. High and low patient BMIs both have shown an increase in anastomotic leak rates. Esophagectomy is most often performed to treat esophageal cancer which has the highest median weight loss of all cancers prior to diagnosis. 7 Malnourished patients should receive 5-7 days of immune-modifying nutritional support to help aid in the reduction of infection rates and anastomotic leaks.5,7 Supplements should be high in protein and include glutamine, arginine, n-3 fatty acids, and ribonucleic acid which are immune-enhancing.5,7 Smoking and alcohol are both major contributing factors to anastomotic leak development as well. Smoking and alcohol cessation is recommended for 4-8 weeks prior to and after surgery.5 57 Hemodynamic management is very important during surgery to maintain adequate tissue perfusion.20 Treatment of hypotension with vasopressors should be avoided if possible because they can have a three to fourfold increase of anastomotic complications.5 Blood transfusions should also be avoided because they can increase the risk of hospital acquired infection and anastomotic leak. 5 Stroke volume, mean arterial pressure, and cardiac output should be used to guide intraoperative fluid administration. 20 Thoracic epidural analgesia can also be used postoperatively to improve microcirculation, and to reduce respiratory complications, the stress response, and chronic pain.7,20 Patients that develop postoperative hypertension and atrial fibrillation should be monitored closely for signs of anastomotic leak because these can also cause reduced blood flow to the anastomosis.39 Similarly, defective glucose control in diabetics can reduce tissue perfusion so blood sugar levels need to be monitored. 3 Atherosclerotic calcifications of the abdominal arteries has been shown to be an predictor of anastomotic leak, and this pathology can be easily seen on preoperative CT scans of the abdomen and incorporated into practice.67 Ischemic preconditioning is a method for improving the microcirculation of the gastric conduit that has seen promising results in experimental settings.52 This area of research is important because gastric perfusion could potentially be improved in patients with known peripheral artery disease, reducing anastomotic leaks.52 Surgically, the most important ways to reduce the risk of anastomotic leak from an esophagectomy include: optimizing perfusion of the conduit, limiting tension to the anastomosis, and using techniques that the surgeon is comfortable and skilled at performing.20 The location of the lesion or pathology that requires resection affects the location of the anastomosis and the surgical method required. Cervical anastomoses tend 58 to have higher rates of leak, but these can potentially be reduced by limiting the tension of the conduit.20 Additionally, cervical anastomoses require a longer conduit rather than the intrathoracic anastomoses, but care must be taken not to place the anastomosis too high on the gastric fundus because of the lower amount of perfusion to this area. 20 Buttressing the anastomoses with an omentoplasty is especially helpful for cervical anastomoses to reduce anastomotic leak rates.57 The omental wrap covers the anastomosis to protect against early leaks and is a source of vasculature for later wound repair.57 The anastomosis can be closed with a handsewn or stapled technique.58 Studies have found that stapling the anastomosis is more favorable in regard to anastomotic leak rates versus a handsewn anastomosis especially in the thoracic esophagus.58 The size of the circular stapler can also affect the rate of anastomotic leak.59 A larger 29mm diameter stapler has a significantly lower rate of anastomotic leak versus a 25 mm stapler.59 Following surgery, it is important to monitor the patient closely for signs of complications. Clinical manifestations of an anastomotic leak may include fever, tachycardia, atrial fibrillation or other arrhythmias, and redness or swelling near incisions.19 Extraluminal surgical drains may indicate anastomotic leaks if there is drainage of bile, gastrointestinal secretions or air.19 Observing changes in serological inflammatory markers such as CRP, WBC, and lactate can be helpful as these may begin to elevate in the presence of an anastomotic leak. 19,30 Diagnostic imaging or endoscopy should be performed as soon as an anastomotic leak is suspected so the proper treatment can be initiated. Imaging of anastomotic leaks is an area that could use more research with the purpose of establishing better guidelines. Currently, it is at the discretion of the clinician as to which exam should be ordered.52 59 Contrast esophagram is a good modality for early or small anastomotic leaks that may be difficult to see on CT, although esophagram has high rates of false-negatives exams with leaks in the cervical esophagus.8 Esophagrams are a dynamic imaging study so patient position can be modified to better challenge the luminal defect. However, there is often significant variability in fluoroscopic technique between radiologists which can produce limitation in the detection of leaks.34 It is helpful for the radiologist to read operative notes prior to performing the esophagram to understand where the anastomosis and the potential leak may be located.34 Computed tomography is advantageous in diagnosing significant leaks and additional findings such as pneumonia, pulmonary embolism or pleural effusion that may be unrelated to a leak.9 Endoscopy is very successful at diagnosing anastomotic leak especially in cases where the patient cannot swallow or for evaluation for conduit necrosis.61 Diagnosis and endoscopic treatment can also take place during the same procedure.61 There are various methods that can be used to treat an anastomotic leak of the esophagus depending on the severity. Minimally symptomatic leaks of the esophagus can be treated conservatively with broad-spectrum antibiotics, NPO status with feeding tube nutrition for 1-3 weeks, and extraluminal drain placement.20 Endoscopy can also place clips that provide closure of small anastomotic leaks. 20 Patients that are more symptomatic are usually treated endoscopically or with interventional radiology by placing a feeding tube, extraluminal drain, and metallic stent to allow the luminal defect to heal. Endoscopy can also use vacuum therapy to promote wound healing.20 Surgery is usually reserved for leaks that have failed more conservative treatments and for leaks that 60 involve sepsis, empyema, local ischemia, or necrosis. Early leaks caused by technical failure are best treated surgically as well.20 Conclusions Anastomotic leak is a feared complication that often has a negative impact on patient outcomes.4 A patient’s overall health and lifestyle can seriously influence the potential for the development of an anastomotic leak. 5 The method of esophagectomy and the techniques used to create an anastomosis are important to ensuring the integrity of the conduit.7 Prompt diagnosis by esophagram, computed tomography, or endoscopy is imperative so that treatments to the defect can be initiated. The high-stakes nature of anastomotic leak and the high morbidity and mortality make experimentation and investigation difficult to accomplish. However, research is needed to establish clinical practice guidelines in the prevention, diagnosing, and treatment of anastomotic leak to improve patient outcomes. 61 References 1. Esophagectomy - minimally invasive: MedlinePlus Medical Encyclopedia. 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