Endoscopic Ultrasound-Guided Treatment beyond Drainage: Hemostasis, Anastomosis, and Others.

Since the introduction of endoscopic ultrasound (EUS) in the 1990s, it has evolved from a primarily diagnostic modality into an instrument that can be used in various therapeutic interventions. EUS-guided fine-needle injection was initially described for celiac plexus neurolysis. By using the fundamentals of this method, drainage techniques emerged for the biliary and pancreatic ducts, fluid collections, and abscesses. More recently, EUS has been used for ablative techniques and injection therapies for patients with for gastrointestinal malignancies. As the search for minimally invasive techniques continued, EUS-guided hemostasis methods have also been described. The technical advances in EUS-guided therapies may appear to be limitless; however, in many instances, these procedures have been described only in small case series. More data are required to determine the efficacy and safety of these techniques, and new accessories will be needed to facilitate their implementation into practice.

INTRODUCTION

Endoscopic ultrasound (EUS) was initially introduced in the 1990s. The radial echoendoscope was used as a diagnostic tool primarily for cancer staging and evaluating surgical resectability. With the advent of the linear array echoendoscope, EUS rapidly developed into a therapeutic instrument used to perform fine needle aspiration (FNA) for cytologic diagnosis. It is now an accepted therapeutic modality with continually evolving indications, including fine needle injection (FNI), drainage of pancreatic fluid collections (PFCs) and abscesses, EUS-guided biliary and pancreatic drainage after a failed endoscopic retrograde cholangiopancreatography (ERCP), and additional innovative techniques that are currently being investigated. In this article, we review the role of therapeutic EUS for gastrointestinal (GI) diseases.

EUS-FNA

EUS-FNA is a simple, cost-effective technique that has been implemented to obtain tissue for the diagnosis of both the GI tract and other areas outside of the GI luminal tract, including pancreatic cysts and masses, GI subepithelial lesions, and lymph nodes.1,2,3,4,5,6 EUS provides a higher sensitivity than both computed tomography (CT) and magnetic resonance imaging, and has proved to be advantageous in reaching a diagnosis after the failure of other diagnostic techniques.1,3,6,7 It enables tissue acquisition of tiny lesions (<5 to 10 mm) that are often too small to be identified with other imaging modalities, or lesions that are encased by surrounding vasculature.8 EUS is now accepted as the first-line diagnostic tool for the above-mentioned lesions.

CELIAC PLEXUS BLOCK AND NEUROLYSIS

Celiac plexus neurolysis (CPN) is the injection of absolute alcohol to destroy the sympathetic plexus near the celiac axis to relieve abdominal pain, traditionally in patients with pancreatic cancer or other malignancies. Celiac plexus block (CPB) is the injection of steroids to inhibit the celiac ganglion function mainly in patients with benign conditions such as chronic pancreatitis. A 19-gauge FNA needle is inserted under EUS guidance adjacent to the lateral aspect of the aorta at the level of the celiac trunk. Aspiration should be performed to rule out needle placement within a vessel. This approach allows visualization of intervening vessels and better visualization of the sympathetic ganglia.9 Absolute alcohol (CPN) or triamcinolone (CPB) is injected into the region of the ganglia under ultrasound guidance. Bupivacaine is also added for initial pain relief.

CPN has a variable reported success rate between 70% and 90%.10,11 Many patients still require the same dose of analgesic; thus, CPN should be considered an adjunct to pain regimens.12 Studies suggest that the EUS-guided approach is superior to CT-guided CPN because the celiac plexus can be easily accessed through a transgastric approach, EUS provides continuous real-time visualization of the target area, and color flow Doppler can be used to avoid regional vasculature.10,11,13 The benefit of repeated CPN was demonstrated in a study of 24 patients; however, the rate of successful pain relief was lower than that for the index CPN procedure (29% vs. 67% at 1 month follow-up).10 CPB appears to have more of a marginal benefit with a reported success rate of 30% to 60% in chronic pancreatitis patients.14 The duration of relief may be up to only 3 months; therefore, it should be reserved for periods of severe pain that had not been relieved by conventional methods such as endoscopic treatment of pancreatic duct strictures or stones.15 The complications of these procedures are fairly rare but include transient hypotension and diarrhea.9

EUS-GUIDED DRAINAGE

Pancreatic fluid collections

PFCs can develop as a result of severe pancreatitis. These fluid collections are categorized, on the basis of the Atlanta classification, as acute fluid collections, pseudocysts, or necrosis.16 Drainage may be indicated if the patient has abdominal pain, rapid enlargement in the size of the collection, biliary or GI tract obstruction, or concern for infection.17,18,19,20,21 In the past, drainage options included percutaneous or surgical approaches; however, EUS-guided transmural drainage of PCFs is now widely reported in the literature. This minimally invasive technique is now considered to be a feasible option for definitive endoscopic treatment. EUS guidance is preferred over the conventional method of endoscopic drainage as it can localize nonbulging collections and can be performed in patients with venous collaterals, those with coagulopathies, and those with a small anatomic window for drainage.22

The linear echoendoscope is advanced into the stomach or the duodenum and is used to locate the PFC. Color flow Doppler is used to localize any regional vasculature. A 19-gauge FNA needle is used to puncture the collection under ultrasound guidance, and fluid is aspirated for culture. A guidewire is coiled within the fluid collection, and dilation of the fistula tract can then be performed. Finally, a stent is placed across the fistula tract for continued drainage. The technical success rate has been reported to be >90%, with a low complication rate of <5%.23,24,25,26,27

Variations have been described in an attempt to streamline this technique. Multiple plastic stents may be placed to promote drainage, with or without a nasocystic drain.25,28 Talreja and colleagues29 described PFC drainage by using covered self-expandable metal stents in 18 patients, with a 95% overall success rate and complete resolution of the fluid collection in 78%. These stents may be advantageous since they provide a radial force that tamponades vessels and have a wider diameter that facilitates drainage; however, stent migration is a concern.30,31 Itoi and colleagues32 described the use of a novel self-expanding, fully covered lumen-apposing metal stent (AXIOS; Xlumena Inc., Mountain View, CA, USA) that appears to be an attractive alternative. The 10-mm-diameter stent has bilateral anchor flanges that are designed to hold tissue in apposition. All cases were reported as successful without complications, although one stent migrated into the stomach without clinical consequence.32

Pancreatic necrosis

Approximately 20% of patients with acute pancreatitis develop pancreatic necrosis.33 Endoscopic pancreatic necrosectomy is now widely described in the literature and increasingly favored over surgical and percutaneous alternatives because of the high rates of morbidity and mortality associated with these options.34 The Dutch Pancreatitis Study Group demonstrated a decreased inflammatory response, rates of organ failure, and major complications in patients undergoing endoscopic necrosectomy compared with those undergoing surgical necrosectomy.35 Although the technique for drainage is similar to that of pseudocyst drainage, endoscopic necrosectomy can be more challenging. Necrosis can contain both solid necrotic material and fluid, and this requires a more aggressive approach with repeated endoscopic debridement and/or nasocystic lavage for successful treatment and resolution.36 Varadarajulu and colleagues37 described the multiple transluminal gateway technique in which a nasocystic catheter is placed into one region of the necrotic collection, and one or more internal drainage sites with multiple plastic stents are created in other regions to drain the collection into the GI tract lumen. This method has been described to enhance the resolution of necrosis, with less need for additional endoscopic or surgical interventions. Sarkaria and colleagues34 described the use of larger-caliber fully covered metal esophageal stents to facilitate the resolution of these collections more rapidly. This technique allowed for quicker endoscopic debridement and passive flow of cystic contents after each session. These technical variations are promising options to facilitate minimally invasive drainage of PFCs and necrosis; however, larger, long-term studies are required to validate the safety and efficacy of these novel approaches.

Abscess drainage

Similar drainage techniques have been applied to abscesses, and have been described as safe and effective. Percutaneous drainage of symptomatic postsurgical abdominal collections has been the standardized approach to avoid repeat surgeries; however, because of the difficult and painful locations, EUS has been introduced to overcome these issues.38,39 This technique has been described for the drainage of gallbladder collections and bilomas,40,41 perirectal abscesses,42 hematomas,43 and postsurgical collections including distal pancreatectomy,43 splenectomy,43,44 and lower anterior rectal resections.43 Singhal and colleagues45 recently published a review of seven cases of EUS-guided liver abscess drainage. The combined technical and clinical success rate was 100%, without complications. Pelvic abscess drainage through the percutaneous approach has long been a conundrum because of the difficult location and access; moreover, it is painful for patients. EUS provides an excellent platform for the drainage of pelvic abscesses, as these collections are often close to the rectum and left colon wall.46 On the basis of the published cases series, this procedure is feasible, effective, and safe, and likely is an excellent alternative to surgical or percutaneous options.42,47,48

There have been varying reports of ideal stent positions and types depending on the collection. There is a suggestion that multiple plastics stents have a prolonged effect; however, the duration of stent placement is also debatable.49 Some authors suggest that the stents should be removed after 2 months;50 however, Ulla-Rocha and colleagues43 chose to leave the stent indefinitely. It is possible that they are expelled into the GI tract once the collections have resolved.24 As there are only small reports of abscess drainage, additional studies are needed to determine the appropriate indications and stents used during the procedure.

Biliary drainage

ERCP is the standard treatment for biliary decompression but can fail in 3% to 10% of cases owing to an inability to cannulate the papilla or an inaccessible papilla due to surgically altered anatomy or duodenal obstruction.51 When ERCP fails, traditional alternatives include percutaneous transhepatic cholangiography (PTC) or surgical interventions; however, these options are associated with increased risks of morbidity and mortality. EUS-guided biliary drainage was first described by Wiersema and colleagues52 in 1996 and is now well described in the literature. It has become a more mainstream therapeutic option in expert centers, with high success rates and minimal complications.

There are various techniques that can be used to drain the bile duct. Access can be obtained by means of a needle puncture and contrast injection of the intrahepatic or extrahepatic bile duct by using an FNA needle. Drainage can be established in either a transpapillary or transmural fashion. Initially, a guidewire is advanced within the duct. The rendezvous technique (retrograde transpapillary drainage) can be attempted if possible, in which case the guidewire is advanced across the papilla and captured with a snare. Retrograde drainage can then be completed. If the wire cannot be advanced across the papilla, then antegrade transpapillary drainage can be performed through direct stent insertion. If transpapillary drainage is not possible, then dilatation of the puncturing tract is performed by using a cystostome or dilating catheter in anticipation of transmural drainage. A plastic or metallic stent is then introduced across the fistula tract.

Recent reviews of the published case series demonstrate a success rate of approximately 90%, regardless of the approach, with an overall complication rate of 16%.53,54 The complications included pneumoperitoneum, bile leak/peritonitis, hemobilia, bacteremia, pancreatitis, abdominal pain, and stent migration.14,53,54,55,56 EUS-guided biliary drainage is rapidly evolving and becoming more common in expert centers; however, the indications and techniques have yet to be standardized. A consortium of world experts first met in 2011, and standardization of the nomenclature, definitions, and indications is currently under way.57

Pancreatic drainage

The development of interventional EUS has also provided better access to the pancreas. Similar techniques can be used to access a dilated pancreatic duct that cannot be drained by conventional ERCP owing to complete obstruction. The main indications include stenosis of the pancreaticojejunal or pancreaticogastric anastomosis after Whipple resection causing acute recurrent pancreatitis, main pancreatic duct (MPD) stenosis due to chronic pancreatitis, postacute pancreatitis, or postpancreatic trauma after a failed ERCP.58

The dilated MPD is localized by using EUS and is punctured with a 19-gauge FNA needle. Initially, a guidewire is advanced in an attempt to cross the anastomosis for a rendezvous. If that is not possible, the needle is exchanged over a guidewire for a diathermic sheath, needle knife, or dilating catheter, which is used to enlarge the transmural fistula. Typically, a 7-Fr pancreaticogastric stent is deployed.

There have been limited numbers of reported cases series, the largest of which was reported by Tessier et al.59 in 2007 and included 36 patients. Owing to the technical complexity of including puncture of the pancreatic duct and stabilization of the endoscope, variable success rates (range, 25% to 100%) and higher complication rates (range, 15% to 50%) have been reported.58 Most technical failures are due to the unsuccessful manipulation of the guidewire, whereas most of the complications are related to the management of the transmural fistula.58 Complications included pancreatitis, abdominal pain, bleeding, perforation, fever, and pancreatic abscess.60 This approach should be reserved for expert endoscopists, and new techniques and accessories are needed to improve outcomes.

Gallbladder drainage

For patients with acute cholecystitis that are not appropriate candidates for surgical intervention, EUS-guided gallbladder drainage (EUS-GBD) has been described to overcome the limitations of percutaneous drainage. It can be used as a bridge to surgery, for palliation in poor surgical candidates after a failed transpapillary cystic duct drainage, and in patients with covered metal biliary stents for malignant obstructive jaundice.61 Initially, transpapillary drainage of the gallbladder with cystic duct stents can be attempted, although this is extremely challenging with low reported success rates (approximately 60% to 80%).40 Alternatively, EUS-guided gallbladder access can be obtained with transmural endoscopic drainage. The resultant drainage may be a temporary measure before cholecystectomy or a long-term palliative option for nonoperative candidates.62 There are no good long-term data on the patency of plastic stents; however, because of the concern for stenosis, standard self-expanding metal stents have been used.63

A recent review of EUS-GBD reported a technical success rate of 97% and a clinical success rate of 100%.61 Jang and colleagues64 reported a randomized control trial comparing EUS-GBD and PTC in 59 patients, demonstrating technical and clinical success rates of nearly 100% in both treatment arms. There was no difference in the rate of complications; however, patients drained by using EUS had significantly lower postprocedure pain scores. Pneumoperitoneum, bile peritonitis, and stent migration have been described in the literature.61,65 To limit these events, a lumen-apposing metal stent Axios (X-Lumena) has successfully been described both in animal models and in the clinical setting.32,66 It also allows access to the gallbladder lumen with slim gastroscopes to obtain biopsies, and facilitate stone removal or debridement.

EUS-GUIDED ONCOLOGIC INTERVENTIONS

Cyst ablation

EUS-guided ablation of pancreatic cysts with chemotherapeutic agents and/or ethanol has shown promising results. Gan and colleagues67 first described this technique in 25 patients in 2005. Eight patients had complete resolution of the cysts, and no complications were reported. Various studies have also confirmed a decrease or disappearance of cyst after ablation on follow-up imaging.67,68,69,70,71

A recent prospective study on EUS-guided ethanol injection with paclitaxel demonstrated that this method is a safe, feasible, and effective treatment for pancreatic cystic lesions.71 Seventy-nine percent of patients showed complete resolution without significant complications. Its use has also expanded to include alcohol ablation of GI stromal tumors (GISTs),72 insulinomas,73 adrenal glands,74 and liver metastasis75 in patients that are poor surgical candidates. This technique remains in debate because it is not clear that patients with these lesions truly require an intervention or whether surveillance would be sufficient. The effect of preventing malignant transformation has not yet been clearly demonstrated.69

Ablation therapy for solid tumors

Radiofrequency ablation (RFA) in pancreatic cancer has been described in surgical and percutaneous methods. EUS-guided ablation has some advantages in that it is less invasive and regions for ablation can be more precisely selected; however, its use is still experimental in animal models.76,77,78,79 Complications such as pancreatitis, gastric wall burn, and adhesion of the surrounding tissue have been reported.78,79 The complications seem to be associated with initial technical problems such as the duration of the ablation or differences between the porcine and human anatomy.79 Carrara and colleagues76,80 recently investigated a new flexible ablation device that combines bipolar radiofrequency with cryotechnology into the porcine pancreas, liver, and spleen. These studies demonstrated the feasibility, efficacy, and safety of EUS-guided ablative therapy; however, further studies are required to determine the effectiveness of EUS-guided RFA in pancreatic cancer and decrease the associated risks.

Photodynamic therapy (PDT) provides localized tissue ablation by using a photosensitizer and light exposure. Photosensitizers accumulate more in tumors than in normal tissue, and light can be generated with small optic fibers that can be advanced through an FNA needle. PDT use in the GI tract was first described in patients with Barrett's dysplasia.81,82 Later, CT-guided percutaneous PDT therapy in patients with unresectable pancreatic cancer was reported.83 Most recently, EUS-guided PDT has been described by Chan et al.84 and Yusuf et al.85 in animal models. Their studies demonstrated localized pancreatic necrosis without significant complications. This, however, needs to be validated.

EUS-guided injection therapy

Advanced pancreatic cancer has a poor prognosis, and no therapy has been shown to increase survival. Localized chemotherapy is gaining favor as it can possibly minimize adverse events related to therapy while increasing therapeutic concentrations within the tumor. Various studies of EUS-guided injection of oncolytic attenuated adenovirus (ONYX-015; Onyx Pharmaceuticals, San Francisco, CA, USA),86 a replication-deficient adenovirus vector carrying the TNF-α gene,87,88 and activated allogenic lymphocyte culture (Cytoimplant; Meyer, Irvine, CA, USA)89 have been described. While these techniques are promising, their efficacy has not been clearly demonstrated.

EUS-guided fiducial placement

A fiducial is an object used as a point of reference for external beam radiation therapy and is available to facilitate radiotherapy for locally advanced pancreatic cancer. The fiducials are loaded within a 19-gauge FNA needle and are deployed to the area of interest by using a stylet or sterile water.90,91,92,93 This technique has a high reported success rate, approximately 90% with <5% migration rate and no significant complications.92,93

EUS-guided brachytherapy

EUS has also been used to place radioactive material into the pancreas for the local treatment of pancreatic cancer. This technique was first described in 1999 and remains limited to small case series.94 In a pilot study, iodine-125 radioactive seeds were injected through a 19-gauge FNA needle with a partial response in 26.7% of patients and minimal effect on pain.94,95 Rare complications such as fever, seed migration, and hyperamylasemia were described. Complications seen in surgical approaches such as GI hemorrhage and pancreatic fistulas were not seen.95,96 This approach has been employed for treating various tumors, including head and neck cancer,97 esophageal cancer,98 and rectal and pancreatic cancer.94,95 The limited results that have been published in the literature are still preliminary, and more studies are needed to determine the efficacy and safety of this technique.

EUS-GUIDED HEMOSTASIS

Endoscopy is effective in achieving hemostasis in most cases of GI bleeding; however, refractory bleeding may occur in up to 15% to 20% of cases.8 These lesions may be amenable to vascular interventions such as angiography, coil embolization, glue application, or transjugular intrahepatic portosystemic shunt.99 Although these procedures have primarily been performed by interventional radiology, more recently, endoscopists have reported their experience of using these treatment modalities with EUS guidance.

With EUS, Doppler flow can be used to identify bleeding vessels and to monitor the success of endoscopic therapy.99,100,101,102 Doppler ultrasound monitored therapy has been successful for recurrent bleeding due to peptic ulcer disease, gastric varices, or Dieulafoy lesions.100,101,102,103,104 It permits direct targeting of the bleeding vessel, accurate delivery of therapy, and confirming cessation of bleeding. It has been suggested that Doppler ultrasound is more accurate than endoscopic stigmata in predicting the risk of rebleeding;99 specifically, the absence of a Doppler ultrasound signal after therapy has been associated with a low risk of rebleeding.105

EUS-FNI of esophageal or gastric varices has also been described in the literature. A prospective study of 54 patients with gastric varices showed that EUS-guided cyanoacrylate injection can obliterate varices.106 Another study of 50 patients with GI hemorrhage due to esophageal varices shows that EUS-guided sclerosis of the perforating veins is more effective than conventional sclerosis techniques.107 Patients with refractory bleeding from hemosuccus pancreaticus, pseudoaneurysms, Dieulafoy lesions, peptic ulcers, or GISTs have been successfully treated with EUS-guided injection of absolute alcohol and/or cyanoacrylate into the bleeding vessel.108,109,110 There have also been reports stating that EUS can be used to deliver microcoils to control refractory bleeding episodes due to varices.99,108,111

Animal models of EUS-guided transhepatic puncture of the portal vein have been described, and the technique preliminarily appears to be feasible and safe.112,113,114,115 These data led to the description of EUS-guided creation of an intrahepatic portosystemic shunt.116 EUS-guided vascular therapy is a new and emerging technique that shows promise for cases of refractory GI bleeding; however, case series are still limited and more data are needed to determine their efficacy and safety.

EUS-GUIDED ANASTOMOSES

Patients with surgically altered anatomy pose a unique challenge when ERCP is required. Several techniques, including enteroscopy-assisted ERCP, surgical techniques, and percutaneous techniques, have been employed but are limited because of technical feasibility and complications. A recent abstract has described a technique of using EUS to create a gastrogastric fistula in patients who have undergone Roux-en-Y gastric bypass. Antegrade ERCP can then feasibly be performed.117

CONCLUSIONS

EUS continues to evolve to perfect minimally invasive techniques both within and outside the GI tract. As the indications for therapeutic EUS continue to expand, larger case series with better long-term data are needed. To increase the success rates and decrease the complication rates associated with these novel techniques, the development of dedicated accessories are imperative.