The gastrointestinal tract provides a unique window to access vascular structures in the mediastinum and abdomen. The advent of interventional endoscopic ultrasound (EUS) has enabled access to these structures with standard fine-needle aspiration. EUS-guided treatment of varices has been largely reserved as rescue therapy for refractory bleeding but has theoretic advantages over conventional endoscopy-guided treatment. Data are limited and multicenter, prospective controlled trials are needed to show clinical effectiveness and safety in humans. The development of new tools designed for EUS-guided vascular therapy is needed.
Introduction
Endoscopic ultrasound (EUS) has developed since the 1980s from a niche tool to an interventional platform that intersects traditional boundaries between interventional radiology and minimally invasive surgery. It has become an essential skill for interventional endoscopists of the twenty-first century. This is exemplified in the developments of pseudocyst drainage and celiac neurolysis that are now well established as key interventions.
Vascular access and therapy are emerging as new targets for EUS-guided interventions. Most major thoracic and abdominal vessels serve as landmarks that guide routine diagnostic and therapeutic EUS procedures. The proximity of these vessels to the gastrointestinal (GI) tract could provide a preferred port of entry into the vascular tree rather than that of traditional femoral, jugular, or subclavian access performed by interventional radiologists.
EUS provides the perfect combination of real-time imaging and minimally invasive interventional endoscopy capabilities. Development of the radial scanning echoendoscope in the 1980s enabled detailed visualization of structures within and outside the GI wall. Real-time visualization of a needle as it is advanced into the target area for biopsy or injection became possible with the advent of the curved linear array (CLA) echoendoscope in the 1990s.
Vessels have been a target for therapy by interventional radiology for several decades. Refractory GI bleeding is treated by selective angiographic embolization. Transjugular intrahepatic portosystemic shunt (TIPSS) is widely used for refractory bleeding esophageal or gastroesophageal varices (GV) associated with portal hypertension. Placement of endovascular grafts is mainstream and the first reports of transaortic valve implantation have emerged. EUS offers an attractive alternative approach to vascular therapy of vessels in close proximity to the GI tract. Major vascular structures, including the heart, aorta, celiac axis, portal vein (PV), hepatic veins (HVs), and mesenteric vessels, and aberrant vascular shunts, such as spenorenal shunts associated with portal hypertension, are easily identified. Even smaller vascular structures, such as the gastroduodenal artery, splenic vessels, hepatic artery, and PV branches, can be confidently traced and identified.
Nonvariceal gastrointestinal bleeding
Endoscopic techniques for nonvariceal GI bleeding effectively treat the majority of the more than 400,000 hospitalizations per year with well-established therapeutic interventions, such as injection of epinephrine, thermal contact therapy, and mechanical hemostasis with clip and band ligation. EUS-guided vascular therapy was first reported in a case series of 5 patients with refractory bleeding from hemosuccus pancreaticus, a Dieulafoy lesion, duodenal ulceration, and GI stromal tumor. These patients had presented with at least 3 bleeding episodes and required multiple units of packed red blood cells and repeated endoscopic and vascular therapies, which were ineffective. EUS-guided injection therapy of absolute alcohol and/or cyanoacrylate (CYA) was delivered directly into the bleeding vessels. Real-time monitoring by Doppler ultrasound was used to conclude the injection therapy when no visible flow could be seen in the bleeding vessel. Control of the bleeding source was achieved in all of these refractory cases without any complications.
Nonvariceal gastrointestinal bleeding
Endoscopic techniques for nonvariceal GI bleeding effectively treat the majority of the more than 400,000 hospitalizations per year with well-established therapeutic interventions, such as injection of epinephrine, thermal contact therapy, and mechanical hemostasis with clip and band ligation. EUS-guided vascular therapy was first reported in a case series of 5 patients with refractory bleeding from hemosuccus pancreaticus, a Dieulafoy lesion, duodenal ulceration, and GI stromal tumor. These patients had presented with at least 3 bleeding episodes and required multiple units of packed red blood cells and repeated endoscopic and vascular therapies, which were ineffective. EUS-guided injection therapy of absolute alcohol and/or cyanoacrylate (CYA) was delivered directly into the bleeding vessels. Real-time monitoring by Doppler ultrasound was used to conclude the injection therapy when no visible flow could be seen in the bleeding vessel. Control of the bleeding source was achieved in all of these refractory cases without any complications.
Esophageal variceal bleeding
Endoscopic band ligation is well established as the preferred technique for primary and secondary therapy of esophageal varices. Injection of sclerosants has been used as rescue therapy. Recurrence is seen in 15% to 65% and thought to be secondary to failure to treat perforating veins and collateral vessels that feed esophageal varices. Krige and colleagues found a correlation between the number of endoscopic sclerotherapy sessions required to achieve eradication and the presence of collaterals. EUS enables the visualization and targeting of perforating veins and collaterals for sclerotherapy. Lahoti and colleagues first reported the use of EUS-guided endoscopic sclerotherapy to achieve variceal obliteration. The sclerosant was injected into the esophageal varices, directed at the perforating vessels until flow was completely impeded. All 5 treated patients achieved variceal obliteration after an average of 2.2 sessions. No recurrent bleeding was reported after a mean follow-up period of 15 months. De Paulo and colleagues reported a randomized controlled trial of 50 patients comparing endoscopic sclerotherapy and EUS-guided sclerotherapy of esophageal collateral veins. They found similar numbers of sessions to achieve obliteration and similar rebleeding rates, but rebleeding was significantly associated with the presence of collateral vessels. A larger randomized trial is needed to determine the potential benefit of EUS-guided sclerotherapy of esophageal varices.
Gastric variceal bleeding
Vascular anatomy of GV is classified into 2 types: type 1 (localized type) consists of a single varicose vessel with almost the same diameter as the inflow/outflow vein, and type 2 (diffuse type) consists of multiple varicose vessels with complex connecting ramifications. GV exist in connection with esophageal varices as 2 types: gastroesophageal varices type 1 (GOV1) are found along the lesser curvature, and gastroesophageal varices type 2 (GOV2) are found at the cardia. Isolated GV (IGV) exist as 2 types: IGV1 are located in the fundus, and IGV2 are sporadic. These distinctions are important in predicting the frequency of bleeding and the response to treatment.
GV are less common than esophageal varices but may be present in up to 20% of patients with portal hypertension. As many as 65% of GV bleed over 2 years. Variceal ligation has performed well in esophageal varices; however, results with GV have not been favorable. Sclerosants have had less success in the treatment of GV, because they are associated with a high incidence of complications, including gastric ulcerations and perforation and recurrent bleeding rates of 37% to 53%.
Direct endoscopic CYA injection of bleeding GV, first described by Soehendra in the 1980s, is widely considered first-line therapy. N-butyl-2-CYA has been used in multiple case series and randomized trials with hemostasis rates of 58% to 100% and rebleeding rates of 0% to 40%. Rengstorff and Binmoeller reported on the use of 2-octyl-CYA in 25 patients with GV with similar hemostasis rates and a 4% rebleeding rate over 11 months.
The major and most serious complication of CYA therapy is systemic embolization. This is well described in individual case reports, including fatal cerebral infarct ( Table 1 ). Entrapment of the needle in the varix by glue and damage to scope have also been reported. The injection technique, including the injection volume and the ratio of the Histoacryl/Lipiodol mixture, was standardized by Soehendra and colleagues based on vitro studies and clinical experience collected in 50 initial cases treated under fluoroscopy.
| See et al, 1986 | Cerebral embolism |
| Gallet et al, 1995 | Cardiac embolism |
| D’Imperio et al, 1996 | Needle stuck in varix, embolism |
| Shim et al, 1996 | PV and splenic vein thrombosis |
| Naga and Foda, 1997 | Pulmonary embolism |
| Cheng et al, 1998 | Splenic vein thrombosis |
| Tsokos et al, 1998 | Pulmonary embolism |
| Rösch, 1998 | Pulmonary, cerebral, coronary embolism |
| Battaglia et al, 2000 | Visceral fistula formation |
| Irisawa et al, 2000 | Left renal vein thrombosis |
| Lo et al, 2000 | Bleeding ulcer, sepsis |
| Hwang et al, 2001 | Pulmonary embolism |
| Türler et al, 2001 | Pulmonary embolism, sepsis |
| Iwase et al, 2002 | Bleeding ulcer |
| Dhiman et al, 2002 | Embolism, needle stuck in varix |
| Tan et al, 2002 | Embolism, sepsis |
| Greenwald et al, 2003 | Pulmonary embolism |
| Sato et al, 2004 | Splenic vein occlusion |
| Wahl et al, 2004 | Recurrent bacteraemia |
| Kok et al, 2004 | Bleeding ulcer, pulmonary embolism |
| Yu et al, 2005 | Splenic artery embolism, splenic infarct |
EUS-guided cyanoacrylate injection
Delivery of CYA under EUS guidance has been previously reported and has the advantage of enabling precise delivery of glue into the varix lumen. EUS also enables assessment of vessel obliteration after treatment with Doppler. This may have prognostic significance, because rebleeding risk after CYA injection has been linked to residual patency of treated varices.
EUS can display the main feeding vein system, which derives from the left gastric vein trunk, posterior gastric vein, short gastric vein, or outflowing vein system with gastrorenal shunts. Romero-Castro and colleagues described a small case series targeting the feeder vessel rather than the varix lumen proper, under EUS guidance. The rationale for targeting the perforating vessel was to minimize the amount of CYA needed to achieve obliteration of GV and thereby reduce the risk of embolization. The investigators targeted the perforating vein using a 1:1 mixture of N-butyl-2-CYA plus lipiodol. The lipiodol enabled fluoroscopic visualization of the injected vessel and confirmation that the feeder vessel had been accurately targeted. There was no rebleeding or complications observed. The limitation of this approach is that identification of the perforating vessel with EUS can be difficult and time consuming, as acknowledged by the investigators. Furthermore, because the perforating vessel may be afferent or efferent, contrast should be injected before treatment to determine directional flow relative to the varix.
An advantage of EUS-guided treatment is the lack of dependency on direct varix visualization. Even in the presence of retained food or blood that may obstruct the endoscopic view, the varix lumen can be accurately targeted for glue injection.
EUS-guided coiling
To avoid issues with glue embolization, 2 small cases series have described deployment of commercially available stainless steel coils. Levy and colleagues used a 22-gauge needle loaded with a microcoil. The stylet was used to advance the constrained coil to the tip of the needle. Once the needle was inserted into the largest (1.4-cm) varix, the stylet was further advanced to deliver the coil. Two additional coils were each placed into separate varices. Rebleeding occurred and repeat EUS therapy was recommended. At EUS, the previously treated varices were thrombosed. Two additional coils were placed into untreated varices. Romero-Castro and colleagues used coils of 0.035 in diameter, 50 mm to 150 mm in length, and with diameters of 8 mm to 15 mm, deployed through a 19-gauge needle. In one patient with a large gastrorenal shunt, the investigators failed to achieve obliteration of GV despite deployment of 13 coils. The investigators subsequently delivered 9 additional coils into the perforating feeding vein. Cost becomes a consideration when using such large numbers of coils to achieve varix obliteration.
Combined cyanoacrylate injection and coiling
In an ex vivo study, the authors deployed a coil in a container of heparinized blood, followed by injection of 1 mL of CYA glue. The glue immediately adhered to the synthetic fibers on the coil and both coil and adherent glue were removed in one piece from the container. Outside the container, the glue was firmly adherent to the coil and no residual glue was identified in the container. The authors hypothesized that the deployment of a coil before CYA injection may serve as a scaffold to retain CYA at the site of injection and serve 2 potential benefits: (1) concentrating the glue at the site of coil deployment and (2) reducing (and possibly eliminating) the risk of glue embolization. Furthermore, the coil itself may contribute to varix obliteration and hemostasis.
The authors reported their first use of coil and CYA as rescue treatment after standard endoscopy-guided CYA treatment failed in a patient with massive gastric fundal variceal (GFV) bleeding. They recently reported experience using a combined approach of CYA injection after deployment of a single coil in a series of 30 patients with GFV. The procedure was successful in all patients, with immediate hemostasis achieved for active bleeding. The average volume of CYA (2-octyl-CYA) injected was 1.4 mL per patient after coil deployment. This was 1 mL less than the average amount injected per patient in a previous study using the same CYA injected alone. There was no damage to the echoendoscope related to glue injections and no procedure-related complications. Of 24 patients with follow-up endoscopy, 23 (95.8%) had complete GFV obliteration after a single treatment session, with no intravariceal flow on EUS color Doppler imaging ( Figs. 1 and 2 ). Recurrent bleeding from GFV developed in 1 patient at 21 days. This patient underwent a second successful treatment with EUS-guided coil and CYA. No patients required surgical or percutaneous shunt procedures.
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