Diagnostic and Interventional Imaging (2015) 96, 731—744

CONTINUING EDUCATION PROGRAM: FOCUS. . .

Transcatheter arterial embolization for acute nonvariceal upper gastrointestinal bleeding: Indications, techniques and outcomes R. Loffroy ∗, S. Favelier , P. Pottecher , L. Estivalet , P.Y. Genson , S. Gehin , J.P. Cercueil , D. Krausé Department of Vascular, Oncologic and Interventional Radiology, Le2i UMR CNRS 6306, University of Dijon School of Medicine, Bocage Teaching Hospital, 14, rue Paul-Gaffarel, BP 77908, 21079 Dijon cedex, France

KEYWORDS Nonvariceal upper gastrointestinal bleeding; Endoscopy; Angiography; Embolization; Surgery

Abstract Over the past three decades, transcatheter arterial embolization has become the first-line therapy for the management of acute nonvariceal upper gastrointestinal bleeding that is refractory to endoscopic hemostasis. Advances in catheter-based techniques and newer embolic agents, as well as recognition of the effectiveness of minimally invasive treatment options, have expanded the role of interventional radiology in the treatment of bleeding for a variety of indications. Transcatheter arterial embolization is a fast, safe, and effective minimally invasive alternative to surgery, when endoscopic treatment fails to control acute bleeding from the upper gastrointestinal tract. This article describes the role of arterial embolization in the management of acute nonvariceal upper gastrointestinal bleeding and summarizes the literature evidence on the outcomes of endovascular therapy in such a setting. © 2015 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

Upper gastrointestinal bleeding (UGIB) is defined as originating in the distal esophagus, stomach, and duodenum (proximal to the ligament of Treitz). The most common cause of nonvariceal UGIB is peptic ulcer disease. Other less common causes include benign and malignant tumors, ischemia, gastritis, arteriovenous malformations such as Dieulafoy’s

∗ Corresponding author. Department of Vascular, Oncologic and Interventional Radiology, Le2i UMR CNRS 6306, University of Dijon School of Medicine, Bocage Teaching Hospital, 14, rue Paul-Gaffarel, BP 77908, 21079 Dijon cedex, France. E-mail address: [email protected] (R. Loffroy).

http://dx.doi.org/10.1016/j.diii.2015.05.002 2211-5684/© 2015 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.

732 lesions, Mallory-Weiss tears, trauma and iatrogenic causes [1,2]. Effective treatment requires timely and accurate diagnosis (location and etiology), and unlike lower gastrointestinal bleeds, most patients have undergone endoscopic examination and treatment prior to their referral to interventional radiology. Of the small group of patients with failed endoscopic therapy, some are treated surgically [3], but increasingly, the majority is referred for embolotherapy [4]. Transcatheter arterial embolization (TAE) has been performed for at least three decades and has been shown to be effective at controlling hemorrhage and decreasing mortality [5—10]. Embolization techniques have evolved with the use of microcatheters and new embolic agents. The purpose of this review is to summarize data on indications, techniques and outcomes of embolization procedures for acute nonvariceal UGIB.

Causes of acute nonvariceal UGIB Several population-based and prospective studies support peptic ulcer disease (PUD) being the most common cause of acute UGIB [11]. PUD refers to either gastric or duodenal ulcers, but under a broad heading of ‘‘ulcers’’ some investigators also include esophageal ulcers. Approximately 50% of all cases of acute UGIB are attributed to PUD [11]. Another recently reported trend in acute UGIB involves cyclooxygenase-2 inhibitors. Cyclooxygenase-2 inhibitors, known for their decreased gastrointestinal toxicity, are extensively used for both their anti-inflammatory and analgesic properties. Population-based studies evidence suggests that the introduction of cyclooxygenase-2 inhibitors may be associated with an overall increased nonsteroidal anti-inflammatory drug use and UGIB [12]. Gastrointestinal hemorrhage can certainly be facilitated when a patient has an endogenous coagulopathic state or is taking anticoagulation therapy. Classically, Mallory-Weiss tears are mucosal lacerations at the gastroesophageal junction or in the cardia of the stomach [13]. These lesions can be associated with repeated retching or vomiting and are another important cause of nonvariceal UGIB. It is estimated that 5 to 15% of all cases of acute UGIB are secondary to Mallory-Weiss tears [13,14]. Vascular ectasias, also referred to as ‘‘angiomas’’, ‘‘arteriovenous malformations’’ and ‘‘angiodysplasia’’, are another source of acute and chronic nonvariceal UGIB [15,16]. Vascular ectasias are the underlying etiology of acute UGIB in approximately 5 to 10% of cases and the severity of bleeding can also range from trivial to severe. Isolated vascular ectasias are endoscopically different from the diffuse linear array seen in gastric antral vascular ectasia, also referred to as ‘‘watermelon stomach’’ [17]. Gastric antral vascular ectasia is thought to be a distinct clinical entity from portal hypertensive gastropathy. Unlike portal hypertensive gastropathy, many patients with gastric antral vascular ectasia do not have portal hypertension [18]. The exact etiology of gastric antral vascular ectasia and its differences from portal hypertensive gastropathy have yet to be fully explained. Dieulafoy’s lesion is a rare etiology in acute UGIB. Dieulafoy’s lesions are difficult to identify endoscopically

R. Loffroy et al. because they often retract. Their histopathologic description is a ‘‘caliber-persistent artery’’ in the submucosal tissue [19]. These lesions are responsible for less than 5% of all nonvariceal UGIB. Neoplasms, both malignant and benign, are another infrequent cause of nonvariceal UGIB contributing to less than 5% of all UGIB cases [20]. Although only a small fraction of UGIB is of neoplastic etiology, this may be the only presenting symptom of a neoplasm, which should be included in the differential diagnosis. The lesion can be a primary malignancy of the esophagus, stomach or duodenum. They may constitute an adenocarcinoma (esophageal, gastric, or duodenal), squamous cell carcinoma (esophagus), lymphoma (gastric or duodenal) or a gastrointestinal stromal cell tumor. Metastases, such as those from the colon, lung, and breast, may also be responsible for UGIB [21]. Examples of benign neoplasms that can lead to UGIB include carcinoid tumors, lipomas, and blue rubber bleb nevus syndrome [22,23]. Other rare causes of nonvariceal UGIB should also be considered in any differential diagnosis. For example, aortoenteric fistula must be considered in patients with a history of intra-abdominal vascular surgery, such as an abdominal aortic aneurysm repair [24]. Hemobilia is another rare cause of UGIB that should be considered in the setting of recent hepatobiliary tree instrumentation, such as with endoscopic retrograde cholangiopancreatography or laparoscopic cholecystectomy. Bile duct and hepatic artery injuries are possible complications of these procedures, and patients can ultimately present with signs of UGIB [25]. In patients with chronic pancreatitis who present with acute UGIB, hemosuccus pancreaticus should also be excluded. Although it is an uncommon cause of UGIB overall, bleeding in these patients can be secondary to a pseudoaneurysm in peripancreatic blood vessels as a complication of pancreatic pseudocysts [26]. Finally, iatrogenic injuries secondary to biopsies or endoscopic procedures, such as percutaneous endoscopic gastrostomy tube placement, are also rare but documented causes of nonvariceal UGIB [26,27]. The main causes of acute nonvariceal UGIB are summarized in Table 1.

Vascular anatomy of the stomach and duodenum The vascular supply to the stomach and duodenum is quite rich, with avid redundant supply. This can make successful embolization more challenging; however, it decreases the incidence of post-embolization ischemia [28]. The likelihood of successful embolization reflects prior knowledge of the location of the bleed. The left gastric artery (LGA) runs along the lesser curve of the stomach and supplies the stomach and distal esophagus. The LGA is most often the first branch of the celiac trunk (90%) but may arise directly from the aorta, as a lienogastric trunk, or hepatogastric trunk [29]. It anastomoses with the right gastric artery (RGA). Small distal branches anastomose with short gastric arteries (from the splenic artery) and the left inferior phrenic artery. The RGA most often originates from the proper, left, or middle hepatic artery but may also arise from the gastroduodenal

Embolization for arterial upper gastrointestinal bleeding Table 1 Causes bleeding.

of

acute

upper

733

gastrointestinal

Etiologies

Percentage

Gastric and duodenal ulcers

35

Variceal bleeding

25

Acute gastroduodenal erosions

15

Esophagitis

10

Mallory-Weiss tears

5

Esophageal or gastric tumors

5

Rare causes Vascular malformations (angioma, ectasia) Dieulafoy’s lesion Aortoenteric fistula Wirsungorrhagia Hemobilia Endoscopic therapy (iatrogenic lesions)

5

artery (GDA) or the right hepatic artery (RHA). It is typically a small vessel that runs in the gastrohepatic ligament and supplies the distal lesser curve of the stomach and the pylorus. The greater curvature of the stomach is supplied by the gastroepiploic arcade (GEA) that courses along the greater curvature of the stomach and is supplied by the right gastroepiploic artery (RGEA), the terminal branch of the GDA, and the left gastroepiploic artery (LGEA), a branch of the distal spenic artery (SPA). A complete arcade (rather than incomplete or weak) is present in about 65% of patients. The duodenum is supplied by the pancreaticoduodenal arcade, supplied by superior and inferior, posterior and anterior pancreaticoduodenal arteries, branches of the GDA and superior mesenteric artery (SMA), respectively. The GDA arises from the common hepatic artery in a large majority of patients, but may also arise from the RHA, a replaced RHA branch of the SMA, or directly from the celiac axis. The vascular dual supply anatomy of the stomach and duodenum is summarized in Fig. 1.

Indications for angiography TAE has become a useful diagnostic and therapeutic tool in selected populations (5—10). The typical candidate patient presents with massive bleeding (transfusion requirement of at least 4 units of blood per 24 h) or hemodynamic instability (hypotension with systolic pressure less than 100 mmHg and heart rate of 100/min or clinical shock secondary to blood loss), who have failed to respond to conservative medical therapy consisting of volume replacement, antacids, H2 receptor blocking agents, or proton pump inhibitors, and have failed at least one, and sometimes two, attempts for endoscopic intervention to control the bleeding [30]. Low risk patients at that point are offered the option of surgical intervention, whereas high-risk individuals are directed towards TAE. Finally, endovascular treatment can be used after open intervention has failed and the bleeding recurs.

Figure 1. Dual vascular supply anatomy of the stomach and duodenum. CHA: common hepatic artery; PHA: proper hepatic artery; SMA: superior mesenteric artery; SPA: splenic artery; GDA: gastroduodenal artery; RGA: right gastric artery; LGA: left gastric artery; GEA: gastroepiploic arcade; ASPD: antero-superior pancreaticoduodenal artery; PSPD: postero-superior pancreaticoduodenal artery.

Angiography procedure Timing of angiography Endoscopy is performed before angiography. Performance of angiography before endoscopy leads to an unacceptably high frequency of unnecessary angiography. Endoscopic diagnosis and therapy can render angiography unnecessary. Endoscopy also helps in planning the timing and approach of angiography. For example, inability to determine the cause of bleeding at endoscopy because of severe bleeding should prompt urgent angiography. Even endoscopic localization of the bleeding site without determination of the cause helps guide which artery to cannulate first at angiography [31]. Negative endoscopic information, such as excluding esophageal bleeding, is valuable to the angiographer. On the other hand, Walsh et al. [32] and Loffroy et al. [30] found longer time to angiography to be predictor of early rebleeding after TAE. They concluded that every effort should be made to perform angiography with embolization early after bleeding onset. Thus, the ability to achieve bleeding control in critically ill patients seems to depend chiefly on early intervention. Finally, the amount of bleeding may affect treatment strategy, continued active bleeding demands for emergency angiography primarily without pre-procedural testing. Defreyne et al. [33] and Whitaker and Gregson [34] independently indicated that the most important determinant of the timing of angiography may be the findings of an experienced endoscopist when faced with nontractable bleeding.

Technique of angiography In the setting of UGIB, the source for hemorrhage is usually identified by endoscopy. Therefore, angiography is most

734 often performed only as a precursor to TAE based on the known vascular supply to the area of abnormality. A positive examination is classically described as extravasation of contrast into the bowel lumen or false aneurysm-like lesion. However, an abnormal blush of the mucosal surface of the upper gastrointestinal tract is indicative of an inflammatory process (gastritis or duodenitis), which, if correlated with endoscopy findings, may also be considered a positive angiographic examination. Angiography in the setting of UGIB is positive for extravasation or abnormal mucosal blush in up to 61% of cases [35]. There is much discussion about the necessity of diagnostic studies preceding angiography. Computed tomography angiography (CTA) has been used accurately (sensitivity up to 86%) in the diagnosis of acute gastrointestinal bleeding and can show the precise location and etiology of bleeding, thereby directing further management [35]. It should probably be performed prior to any invasive procedure in the absence of hemodynamic instability, even if its use is less important than for lower gastrointestinal bleeding since endoscopic localization of the bleeding site is the rule in most cases at the upper tract, helping guidance for TAE, even in the absence of extravasation. By the time a patient with UGIB reaches the interventional suite, he should be fluid-resuscitated, hemodynamically stable and have any coagulopathy corrected. Blood products such as fresh frozen plasma, platelets, or packed red blood cells may also be given intraprocedurally. It is desirable to correct any coagulopathy before embolization, because achieving hemostasis depends on technically successful embolization as well as the patient’s ability to clot properly. However, in case of acute bleeding, an arteriography with embolization should be promptly performed and soon followed by coagulopathy correction. A transfemoral approach is mostly used and involves placement of a 5French sheath in the common femoral artery. A variety of introducers and selective catheters with a smaller caliber can be used to cannulate the celiac artery and obtain access to common hepatic artery. For selective catheterization via the femoral route, the most widely used catheter configurations are the cobra, hook, and short- and long-curve sidewinder with a diameter of 4-French. Once access is secured, arteriogram is performed to delineate the anatomy and identify contrast extravasation. Selective catheterization for UGIB includes the celiac and superior mesenteric arteries. The initial artery catheterized is the one most suspected of bleeding based on prior imaging or endoscopy, which is of course the celiac for UGIB. If no extravasation is seen, then superselective angiography is advised, depending on endoscopic findings that offer information on the likely location of the bleeding source: superselective catheterization of the GDA, the LGA, or the splenic artery may be performed. A microcatheter is always necessary for a distal and superselective approach to the bleeding as well as for avoiding the spasm caused by catethers with a 4-French or 5-French caliber. Longer injection durations or use of carbon dioxide for contrast medium can also improve sensitivity for small bleeds. Arteriography after superselective cannulation may reveal extravasation that could have been missed during contrast injection in the main hepatic artery. When a dual supply of the bleeding area is suspected, both arterial sources need to be

R. Loffroy et al. embolized to assure that all the inflow ceases. This is the typical case of bleeding secondary to an ulcer that erodes into the gastroduodenal artery; embolization in this case needs to start distally to prevent persistent ‘‘back-door’’ hemorrhage from the right gastroepiploic and superior pancreaticoduodenal arteries, and proceed in the proximal side of the erosion.

Provocative angiography We do not believe there is enough data to provide definitive guidelines to perform provocative mesenteric angiography or pharmacoangiography. Furthermore, this technique is mainly used to provoke lower GI bleeding, which is more challenging than UGIB. Indeed, contrary to lower GI bleeding, almost all upper gastrointestinal bleeders have undergone endoscopy in an attempt to identify, localize and treat the source of bleeding. Several prior studies have shown that empiric embolization based on endoscopic findings, in the absence of contrast extravasation, can be performed safely and successfully [36,37]. So the absence of angiographic extravasation is less problematic at the level of the upper gastrointestinal tract and does not prevent from embolizing the artery that supplies the bleeding site. However, this technique can be applied in situations where conventional angiography is nondiagnostic. The addition of pharmacologic agents to standard angiographic protocols in order to increase the diagnostic yield has been reported in case reports and small series. Provocative mesenteric angiography is the use of thrombolytic, vasodilating, and anticoagulation medications to elicit active bleeding from a source that may have recently ceased hemorrhaging. Unfortunately the available literature on this topic is limited. Koval et al. [38] doubled the rate of extravasations visualized by angiography from 32 to 65% with the introduction of pharmacologic angiography. Malden et al. [39] and Ryan et al. [40] separately showed a provoked bleeding rate of nearly 40% when previous angiograms had been normal with a minimal complication rate. Although reasonably successful and without any reported major hemorrhagic complications, provocative mesenteric angiography is not a commonly used examination. The precise reasons for this are unknown but likely relate to fear of potential uncontrollable hemorrhagic complications and lack of familiarity with this procedure by referring clinicians and interventional radiologists. Both of these are likely a reflection of the sparse data supporting provocative mesenteric angiography in the literature. Basically, provocative angiography may increase the diagnostic ability when a normal angiogram is encountered for nonvariceal UGIB. But several procedure-related factors may affect the diagnostic yield of provocative studies; these include timing of the procedure, the type and dosage of provocative medications, and the expertise of the operators. The types of pharmacological provocation reported in the literature have been variable [41—45]. Based on these data, an idealized protocol could include intra-arterial tolazoline at a dose of 25 mg, intra-arterial heparin at a dose targeted to double the patient’s baseline activated clotting time, and intra-arterial urokinase in aliquots of 250,000 U given over 15 min and monitored by diagnostic

Embolization for arterial upper gastrointestinal bleeding angiography. Endpoints are either hemorrhage or a total of 1,000,000 U of urokinase over an interval of approximately 1 hour. However, it should be emphasized that the specific agents and their total doses in literature are largely arbitrary. Currently, provocative angiography is rarely needed for the diagnosis of GI bleeding and only limited reports for use in difficult and recurring nonvariceal UGIB have shown to be beneficial. We believe that further prospective studies are required to provide a better understanding of optimal patient selection and optimal pharmacological provocation. Only with these kinds of data can provocative gastrointestinal bleeding studies be appropriately placed in a diagnostic algorithm for evaluation of patients with gastrointestinal hemorrhage of obscure origin.

Embolization procedure Over the past three decades, angiographic interventions have shifted from playing a purely diagnostic role to being a major therapeutic option in the management of nonvariceal UGIB. Transcatheter intervention to control gastrointestinal bleeding takes two forms: the infusion of a vasoconstricting medication and the mechanical occlusion of the arterial supply responsible for the hemorrhage.

Intra-arterial vasopressin infusion Selective infusion of intra-arterial vasoconstrictors was one of the first angiographic treatments for gastrointestinal bleeding. Vasopressin, a posterior pituitary hormone, elicits smooth muscle contraction in the mesenteric bed, thereby decreasing the perfusion pressure to the bowel and potentially resulting in thrombosis of the bleeding site. Vasopressin infusion is easy to perform, most often by placing a 5-French diagnostic catheter into the artery most suspected of bleeding [46]. Vasopressin is then infused at a rate of 0.2 to 0.4 U/min until successful control of bleeding is observed on angiography. Then, the mesenteric intraarterial infusion is continued for 12—48 hours. Vasopressin infusion has lost favour for two main reasons: necessary catheterization times can require several days and, more importantly, the emergence of embolotherapy. For nonvariceal UGIB, the offending arteries were easily accessible even with large and crude catheter systems and embolic agents of the past. In addition, given the rich arterial collateral network and proximal site of embolotherapy, ischemia was not thought to be problematic. Given that embolotherapy replaced vasopressin infusion early in the treatment of UGIB, there is little recent data on the use of this technique. In addition, much of the data include treatment of variceal bleeding. A review of four of the recent studies consisting of 267 patients demonstrated an initial 70 to 80% success rate. They observed approximately 20% rate of rebleeding with hemorrhage refractory to infusion in up to 40% of patients [47,48]. Failures of vasopressin are thought to be due to the rich collateral supply to the upper gastrointestinal tract and the inability to treat potential collateral supply pathways to the bleeding site, but this is unproven. Finally, the use of vasopressin in the treatment of nonvariceal UGIB is empiric as there is no substantial data to support its use [48].

735

Transcatheter selective embolization Technique Because of the high rebleeding rate with infusion therapy, other angiographic interventions were developed to treat nonvariceal UGIB. As is true of most other minimally invasive and image-guided interventions, embolotherapy has supplanted surgery in most centers as the treatment of choice for endoscopy-refractory UGIB. This method is associated with an initial bleeding control rate of 89—98%. Clinical success rates rang from 52—98% with most reports showing success rates of 70—80% [30,33,36,49,50]. The role of TAE is to selectively reduce blood supply at the source of bleeding while maintaining enough collateral blood flow to maintain intestinal viability. Typically, in cases of active hemorrhage with extravasation of contrast, the bleeding vessel is identified by superselective catheterization using a microcatheter and embolized with microcoils, particles or glue if arterial flow is not blocked by the microcatheter (Fig. 2). Superselection and embolization of short segments of visceral arteries can be performed with newer advances in hydrophilic steerable wires, microcatheters and embolic agents. Coaxial systems allow 2 to 3-French catheters to pass through larger primary catheters to allow access to distal arterial branches. In general, bleeding in the esophagus and fundus of the stomach is treated by embolization of the LGA (Figs. 3 and 4). Bleeding in the body and antrum of the stomach may be controlled by embolization of either the gastroepiploic, right gastric or gastroduodenal arteries depending on the source of bleeding.

Blind or empiric embolization Blind embolization is controversial. Because massive bleeding is often intermittent, most groups have adopted a policy to embolize on the basis of endoscopic findings even in situations that no extravasation is seen angiographically. In the series from Aina et al. [36], Loffroy et al. [30], and Padia et al. [37] there was no difference of outcome between patients who underwent blind embolization and those who underwent embolization after a bleeding site had been demonstrated angiographically. Other researchers also advocate the practice of endoscopy-directed blind embolization [32,33]. Based on the findings from the literature and our own experience, we believe that blind embolization is appropriate. The GDA should be embolized using the ‘‘sandwich technique’’, in which both ends of the artery are filled with coils to avoid retrograde bleeding from the superior mesenteric circulation (Fig. 5). If there is suspicion that smaller muscular branches terminating to a clip are the culprits, then those should be embolized with any of the materials available. The ‘‘back-door’’ from the SMA has to be checked angiographically after embolization of the GDA to make sure there is no retrograde filling of the bleeding site (Fig. 6).

Choice of embolic agent Many embolization agents have been used successfully: coils, particulate material such as resorbable gelatin sponge, and nonresorbable polyvinyl alcohol (PVA) or tris-acryl gelatin particles. Liquids such as N-butyl

736

R. Loffroy et al.

Figure 2. Arteriogram images of bleeding from a bulbar duodenal ulcer in a 76-year-old man: a, b: arteriogram showing contrast medium extravasated from a slender branch of the gastroduodenal artery into the duodenum (arrows); c, d: after microcatheterization, selective glue embolization (radiopaque because of associated lipiodol (arrow)) preserving the gastroduodenal artery ensured control of the bleeding, with no early or late recurrences.

Figure 3. Bleeding Dieulafoy’s lesion in an 87-year-old man: a, b: extravasation of contrast medium from the left gastric artery at the celiac trunk and superselective angiography indicates continuing bleeding (arrows): c: after arterial microcatheterization, bleeding was controlled after embolization of the left gastric artery using a Glubran® 2/lipidol mixture (1:3) (arrows).

Figure 4. Acute esophageal bleeding from the cardia in a 45-year-old man with hypovolemic shock: a: endoscopic view showing a circumferential hemorrhagic esophagitis of the distal part and the cardia; b: angiography demonstrating small esophageal branches arising from the LGA without extravasation; c: control after blind selective embolization with glue, guided by clips. The bleeding was stopped immediately without recurrence.

Embolization for arterial upper gastrointestinal bleeding

737

Figure 5. Typical sandwich embolization in a 73-year-old woman with bleeding from a postbulbar duodenal ulcer at endoscopy: a, b: global and selective angiography before embolization: no evidence of active bleeding, c: coil embolization of the distal and proximal gastroduodenal artery (with gelatine sponge in the arterial trunk), including the anterior and posterior superior pancreaticoduodenal arteries and the right gastroepiploic artery, to prevent retrograde flow (arrows). Bleeding stopped and no ischemic complications were reported.

2-cyanoacrylate (NBCA) glue (Glubran® , GEM, Viareggio, Italy) or ethylene-vinyl alcohol copolymer (Onyx® , Micro Therapeutics, Inc., Irvine, CA, USA) are less popularly used [30,33,36,49,51]. The choice of the best embolic agent is still debatable. Embolotherapy in these emergency patients has to be fast, easy to perform and effective. Success is achievable with different materials in experienced interventional radiologist’s hands. Coils alone inserted in the GDA or superselectively in the pancreaticoduodenal arteries have been used with success

by several investigators [33,50,52]. When used in the setting of UGIB, coils are usually used to occlude or reduce flow into a major vessel, which can also be treated at a more distal level with a particulate agent (usually gelatin sponge) to aid in hemostasis. The main advantages of using coils are that they can be delivered in a very precise fashion and carry low risk of infarction because of the preservation of the distal microvasculature. Coils and microcoils of different size and length can be used. They may have thrombogenic fibers to facilitate occlusion of the vessel, and they

Figure 6. Images of bleeding from a duodenal ulcer in a 68-year-old man: a: angiography before embolization, guided by metallic clips, showing bowel hyperhemia; b: glue embolization of the GDA after protection of the RGEA with coils to avoid distal embolization of the GEA; c: check control of the SMA showing ‘‘back-door’’ bleeding from a proximal jejunal branch with extravasation at the initial bleeding site; d: results after superselective embolization with Glubran® 2-cyanoacrylate glue, without rebleeding.

738 may offer the option of detachability and retrievability. The main drawback is that they are permanent and may preclude re-accessing the vessel in the future should it prove necessary. Another disadvantage is that coil application is dependent upon vessel diameter and intrinsic blood clotting. That is probably why Aina et al. [36] and Loffroy et al. [30] showed an association between the use of coils alone and the incidence of bleeding recurrence, especially in patients with coagulopathy. The advantages of use of PVA or gelatin sponge in association with coils when choosing a strategy for this subgroup of patients cannot be over stressed. Gelatin sponge is the main temporary embolic agent used worldwide. It has the advantage that after resorption, flow will be restored weeks after embolization. Furthermore, it is readily available, cheap, and unlikely to cause ischemia. The disadvantages are that it requires some time to prepare appropriate-sized particles, and the pace of recanalization is unpredictable. Lang et al. [6] compared several embolic agents in a series of 57 patients. They reported that a high rate of bleeding recurrence was observed when gelatin sponge was used alone. Similarly, Encarnacion et al. [8] achieved a low success rate (62%) in their series, which included mostly patients embolized with gelatin sponge alone. These data confirm that the use of gelatin sponge as the only embolic agent guarantees only short-term results and should probably be avoided. Particles such as PVA particles and tris-acryl gelatin microspheres may be of advantage when a flow-directed strategy is favourable, e.g. when diffuse tumor vascularization is to be excluded from the arterial supply. These agents have been used successfully in treating gastrointestinal hemorrhage, usually through a microcatheter and at a site distal to major vessels [53]. Only larger particles (>500 ␮m) should be used to decrease the risk of ischemia from normal tissue devascularization. More recently, very good results have also been reported with NBCA [54—57]. Toyoda et al. [56] reported that the time required for TAE using NBCA was significantly lower than for TAE procedures that do not use NBCA. This is important especially in cases of massive bleeding that require urgent hemostasis. Indeed, the use of NBCA glue is particularly of interest in hemodynamically unstable patients and in cases of underlying coagulopathy. A number of institutions have adopted selective embolization using glue as the only embolic agent as the salvage treatment of choice in UGIB cases. However, the use of NBCA glue requires training and considerable experience, given the risk of bowel infarction and glue reflux into other vessels. Reflux of NBCA may also result in its polymerization to the catheter tip. This bit of NBCA may then be stripped from the catheter during catheter retraction, resulting in nontarget embolization. The use of a proper technique, including prompt removal of the catheter after injection as well as aspiration of the guide catheter after microcatheter removal, can significantly reduce this risk [58]. Another drawback is the potential risk of bowel stenosis over the long-term. Lang [53] found a 25% duodenal stenosis rate in a study of 28 patients that were followed up for at least five years after embolization for bleeding duodenal ulcers, even if the link between glue embolization and duodenal stenosis is difficult to evaluate. Onyx® seems to have great potential as a liquid embolic agent in embolotherapy of acute UGIB. Lenhart et al. [51]

R. Loffroy et al. and Urbano et al. [59] recently reported their experience with the use of Onyx® in such a setting. Their studies represent the first series to date reporting results on arterial embolotherapy with Onyx® as an embolic agent in the gastrointestinal tract. The success rate was high (81%) and the complication rate was almost nil. The main advantages of Onyx® are its nonadhesive properties, high radiopacity, and long solidification periods. These properties of Onyx® compared to acrylic glues, make the embolization procedure more controllable and predictable [60]. However, Onyx® has some disadvantageous characteristics. First, DMSO can cause severe vasospasm if injected rapidly. Secondly, DMSO is volatile and is excreted via respiration and sweat. This has a typical smell not unlike that of diabetic ketoacidosis and may last a few days. The patient and ward staff should be warned to expect this. Lastly, the use of Onyx® has cost implications as it is much more expensive than alternative embolic materials and requires specific DMSO-compatible microcatheters. These factors explain its restricted use in neuroradiology in most of the institutions around the world. In some situations, specific endovascular techniques may be useful to stop bleeding as coil packing of a pseudoaneurysmal sac (Fig. 7) or implantation of a covered stent (Fig. 8), in order to preserve the patency of the parent vessel. Finally, it is not clear if careful selection of the embolic agents according to the bleeding vessel may play a role in a successful outcome. It would be worth comparing the different embolic agents for arterial embolotherapy in the gastrointestinal tract in a prospective randomized multicenter trial. However, data from the literature suggest that coils probably should not be used as the only embolic agent, but rather in association with gelatin sponge, particles or glue for the treatment of gastroduodenal hemorrhage. Furthermore, surgical glue should probably be used more often, especially in patients with coagulopathy, because it provides a better and faster hemostasis and does not cause ischemia.

Marking with a metallic clip Eriksson et al. [61] reported a series of 10 patients who were referred for embolotherapy after failed endoscopic attempt to control bleeding from acute duodenal ulcer. In order to guide the endovascular treatment, the endoscopists marked the site of bleed with clips placed at the junction of the ulcer and the adjacent normal mucosa. In eight patients hemostasis was achieved after embolization, whereas surgical intervention was necessary in the other two. The clips accurately guided the endovascular intervention in six patients who had no evidence of contrast extravasation at the time of angiography. This was of particular importance in three patients; in two the culprit vessel was a supraduodenal artery without connection to the GDA, whereas the third was bleeding from erosion into the inferior pancreaticoduodenal artery that was arising from the superior mesenteric artery. Marking with a metallic clip can assist with localization of the vessel feeding the bleeding ulcer even if there is no contrast medium extravasation after injection with the catheter in the common hepatic or the main trunk of the GDA. This is also important when the bleeding artery arises separately from the proper hepatic artery or the GDA. Superselective angiography guided by clip position has

Embolization for arterial upper gastrointestinal bleeding

739

Figure 7. A 41-year-old woman presented three weeks after laparoscopic cholecystectomy with right upper abdominal pain and hemobilia: a: computed axial tomography scan: round mass within the gallbladder fossa that shows contrast filling at the arterial phase (arrow), and dilatation of the bile duct (arrowhead); b: selective hepatic arteriogram demonstrating pseudoaneurysm of the cystic artery stump; c: coil embolization of the aneurysmal sac across the neck using the packing technique through a microcatheter; d: control angiography showing complete occlusion of the false aneurysm and preservation of the main and distal hepatic artery.

better chances to demonstrate the extravasation, making blind coil placement unnecessary, increasing the efficacy of the procedure and reducing the risk of coil misplacement and inadvertent hepatic embolization. The only limitation

of this technique is the need for around the clock availability of an experienced interventionalist and gastroenterologist, which is easy to achieve only in high volume medical centers.

Figure 8. Wirsungorrhagia in a 72-year-old woman with acute pancreatitis: a, b: CT scan of the abdomen showing a pseudoaneurysm of the splenic artery communicating with the wirsung duct which is opacified at the arterial phase; c: angiography confirms a pseudoaneurysm of the middle part of the splenic artery partially thrombosed; d: results after implantation of a covered stent showing complete exclusion of the lesion.

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R. Loffroy et al.

Outcomes Procedural and clinical outcomes In a review by Loffroy et al. [49], 15 studies (819 patients, mean age 65 years) on endovascular management of intractable nonvariceal UGIB were identified. Endoscopy had been performed and failed in 99% of patients. The vast majority of patients treated endovascularly in the series had significant comorbidities and was deemed high risk for operative intervention. Endovascular embolization was successful technically in 93% of patients. The causes for endovascular technique failure were as follows: difficult vascular anatomy, arterial dissection, vasospasm, false negatively read angiogram, multiple bleedings, and tumorous bleeding. A variety of embolic materials were used. The ‘‘sandwich’’ technique with placement of embolic material at both sides of the bleeding vessel was utilized in most series, in order to minimize the chance of recurrent bleeding due to rich collaterals. Active extravasation was present at the time of embolization in only 54% of patients. Consequently, 46% of patients underwent blind embolization, guided by the findings of endoscopy or placement of clips around the area of the bleeding vessel. In most cases, gelatin sponge or coils were then used for embolization. From the subgroup that underwent technically successful embolization, 67% of patients responded well clinically with cessation of bleeding. Thirty-three percent of patients continued to bleed but almost half of them responded to repeat embolization. Finally, 20% of patients underwent open surgical intervention to definitively manage the bleeding source. Major and minor embolization-related complications developed in 9% of patients and included access site complications, dissection of the target vessel, and liver and spleen infarction. The most significant long-term complication was duodenal stenosis in a series by Lang [53], particularly after

glue embolization of terminal muscular branches of the gastroduodenal artery (25%). Overall 30-day mortality was 28%. The causes of death were underlying conditions in most cases. Although the mortality appears to be as high as in some surgical series for emergent open repair of UGIB, one should keep in mind that the patients treated with embolotherapy had been, in most occasions, turned down for open repair due to significant comorbidities and advanced age. A closer look into this review of outcomes and the individual studies underscores a few important points. First, mortality and complication rates exhibited wide variability among series, further emphasizing the importance of individual expertise and center experience in outcomes. Second, the presence of active extravasation and superselective embolization does not necessarily imply better short-term clinical response, a phenomenon that may be explained by the intermittent nature of the gastrointestinal bleeding, and the presence of bleeders that were missed with the very selective embolotherapy. Last, only 20% of the patients who initially underwent embolization finally needed surgical intervention to control recurrent bleeding, indicating that embolotherapy can reduce the incidence of laparotomy in patients presenting with acute UGI bleeding. Surgery was usually performed after failure of second endoscopic hemostasis or embolization procedure at the discretion of the gastroenterologists or surgeons. Main results are summarized in Table 2.

Complications Groin hematomas (3 to 17%) and contrast-related complications (0.04 to 12.7%) can occur with the same frequency as in other endovascular procedures [49]. Acute renal failure may occur and its etiology is multifactorial, related to the contrast injection in the context of hemorrhage and volume depletion. Arterial embolization in the upper gastrointestinal tract above the ligament of Treitz is

Table 2 Outcomes in main published series of angiographic embolization for acute nonvariceal upper gastrointestinal bleeding. Reference, year

Clinical success (%)

Rebleeding rate (%)

Need for surgery (%)

Complication rate (%)

30-day mortality (%)

Lang [53], 1992 Encarnacion et al. [8], 1992 Toyoda et al. [56], 1996 Walsh et al. [32], 1999 Schenker et al. [73], 2001 Defreyne et al. [33], 2003 Aina et al. [36], 2001 De Wispelaere et al. [74], 2002 Ripoll et al. [68], 2004 Holme et al. [9], 2006 Loffroy et al. [52], 2008 Larssen et al. [75], 2008 Poultsides et al. [76], 2008 Loffroy et al. [30], 2009 Padia et al. [37], 2009

86 62 80 52 58 60 73 64 71 65 94 72 51 72 44

56 11 23 52 29 37 23 36 29 28 17 9 47 28 66

2 17 13 37 NA 26 16 21 16 35 14 30 21 12 21

16 17 NA 4 10 20 5 0 0 0 6 8 26 10 5

4 45 23 40 33 30 35 46 26 25 21 17 21 27 20

NA: not available.

Embolization for arterial upper gastrointestinal bleeding generally considered very safe because of the rich collateral supply to the stomach and duodenum. However, the risk of significant ischemia after embolization is known to increase in patients with previous surgery within the same area [32] or with embolic agents that can advance far into the vascular bed such as liquid agents (e.g., tissue adhesives as cyanoacrylate) or very small particles (e.g., gelatin sponge powder or calibrated microspheres) [32,34]. Although cases have been reported at the acute phase, post-embolization ischemia usually presents as duodenal stenosis at the chronic phase. Lang [53] reported duodenal stenosis in seven of 28 patients 8 months to 7 years after embolization of terminal vessels, mostly when tissue adhesive was used. In this series, duodenal stenosis after GDA embolization was far less common and occurred in only two of 29 patients who underwent more proximal GDA occlusion. The high incidence of stenosis of the duodenum attendant upon embolization of the terminal vessels of a bleeding site is thought to be the consequence of severe hypoxia and resultant avascular necrosis. Surgical correction of the stenosis was necessary in eight patients to address persistent symptoms. Another patient had to undergo multiple balloon dilatations for duodenal stenosis. Balloon dilatations were performed in one additional patient after surgical resection and recurrent symptoms of duodenal obstruction. Inadvertent embolization of the main hepatic artery can result to a broad spectrum of manifestations, ranging from a temporary increase in the liver enzymes, to life-threatening hepatic failure, the latter being more common in the setting of cirrhosis and associated compromise of the portal vein circulation. Inadvertent placement of coils in the main branches of the celiac axis has been reported (up to 3.3%) [49], usually in keeping with technical difficulty or coil migration. Given the rich collateral circulation, however, coils in the left gastric or splenic artery rarely produce organ-threatening ischemia [49].

Predictors of success and survival Although few published series analyzed factors predicting embolization failure, there are now enough data on factors that may influence the outcome of patients who have undergone embolization procedures for acute UGIB [49]. Among clinical predictors of rebleeding, coagulopathy has been shown to adversely affect the success rate for embolotherapy, with an increase in the odds ratio for clinical failure, which ranges from 2.9 to 19.6. Consequently, every effort should be made to correct coagulopathy before, during, and after intervention. Other clinical variables have been identified as predictors of early rebleeding after embolization. Several of the variables that were studied in our largest series such as coagulation disorders, a longer time from shock onset to angiography, a larger number of RBC units transfused before angiography, and having ≥2 comorbid conditions were found to be associated with early rebleeding [30]. Thus, the ability to achieve bleeding control in critically ill patients seems to depend chiefly on early intervention and severity of the underlying disease. Previous surgery for bleeding is also a well-documented independent predictor of poor embolization outcome [32].

741 Clinical signs of shock and active bleeding at admission are known risk factors for rebleeding after endoscopic therapy; hence, they are probably risk factors for early recurrence after embolization as well [62,63]. Corticosteroid use is more often encountered in inpatients with bleeding than in those with primary-referred UGIB, but it has not yet been reported to be an independent risk factor for rebleeding. Factors influencing mortality include advanced age, trauma or sepsis, recent major operation, lung or liver disease, and massive blood transfusions. A number of factors have been identified as influencing post-embolization mortality. One of the most important and frequently encountered is the absence of early recurrent bleeding. A strong correlation has been seen between coagulopathy, clinical failure, and mortality after embolization [49].

Topics of interest Embolization versus surgery To date, there has been no controlled trial that compared angiographic embolization to surgery as a salvage procedure for failed endoscopic therapy. The wide array of alternatives for the treatment of UGIB after endoscopic failure make the decision of when to resort to emergency surgery more difficult, especially in patients with risk factors for recurrent bleeding and death that are also related to high surgical risk. Lau et al. [64], in a randomized controlled study, showed no differences in bleeding control between a second endoscopic treatment and surgery after initial endoscopic treatment failure for bleeding peptic ulcers. During endoscopy, active bleeding, large ulcer size, location of ulcer at posterior bulbar duodenum, and lesser curve are identified as predictors for endoscopic failure [49]. Embolotherapy may be particularly attractive in such a setting because it is not as invasive as surgery and has few complications. Another advantage of TAE is that most of the patients with recurrent bleeding after initial treatment with surgery or TAE, can be effectively treated with TAE, avoiding a second surgical procedure. Despite the retrospective, observational design of the study by Ang et al. [65], the authors provide important, clinically relevant data that advances our knowledge in how we should be caring for patients with UGIB. The findings in this study appear to confirm previously published retrospective case series that support the role of TAE and show it reduces the need for surgery, has a low complication rate, and does not increase mortality [66—69]. Indeed, four other retrospective studies compared the two techniques and showed at least similar efficacy in terms of rate of rebleeding, morbidity, and mortality, whereas there was a bias of selection since TAE was preferentially used for high surgical risk patients. These data suggest that surgery would have probably been catastrophic in this patient population and that TAE offered better results [70]. Ripoll et al. [68] retrospectively analyzed the outcome of 70 patients with refractory peptic ulcer bleeding. Thirty-one patients underwent TAE, and 39 patients were managed with surgery. Although patients receiving TAE were 10 years older, and more patients had heart disease and coagulation disorders, the incidence of

742 recurrent bleeding (29% versus 23%) and mortality was similar (26% versus 21%). Another retrospective comparison study by Eriksson et al. [69] included 40 patients who underwent TAE and 51 patients who underwent surgery after failed endoscopic therapy. The TAE group was older and had more comorbidity. Thirty-day mortality was lower in the TAE group (3% versus 14%). More recently, Venclauskas et al. [67] compared these two treatment strategies. Arterial embolization was performed in 24 patients and open surgery in 50 patients after unsuccessful endoscopic therapy for bleeding duodenal ulcers. The mean age and acute physiology and chronic health evaluation II score were significantly higher in the embolization group. Only mortality in highrisk patients was significantly lower in the TAE group (23.1% versus 50%). In a retrospective comparative study by Wong et al. [15], the 30-day mortality was high, 25% in the TAE cohort and 30.4% in the surgery cohort, yet these mortality rates were not statistically different. The majority of deaths in both cohorts were from nonbleeding related causes. In the TAE group, there were significantly fewer postprocedure complications, and no procedure-induced ischemic events. The rebleeding rate noted with TAE (34.4%) was not different from what has been reported elsewhere in the literature. Other measured patient outcomes including total length of hospital stay, length of hospital stay postprocedure, and units of blood transfused were no different between the TAE and surgery groups. These results are promising, and we are eagerly awaiting results of the randomized controlled trial from the Hong Kong team (NCT00766961) [71], which is currently recruiting to prove the benefits of TAE.

Prophylactic embolization in high-risk peptic ulcer bleeding One of the major challenges in peptic ulcer bleeding is rebleeding which is associated with up to a five-fold increase in mortality. Recently, Laursen et al. [72] examined if supplementary transcatheter arterial embolization (STAE) performed after achieved endoscopic hemostasis improves outcome in patients with high-risk ulcers. The study was designed as a non-blinded, parallel group, randomized controlled trial and performed in a university hospital setting. Patients admitted with peptic ulcer bleeding from Forrest Ia—IIb ulcers controlled by endoscopic therapy were randomized (1:1 ratio) to STAE of the bleeding artery within 24 h or continued standard treatment. Randomization was stratified according to stigmata of hemorrhage. Patients were followed for 30 days. Primary outcome was a composite endpoint where patients were classified into five groups based on transfusion requirement, development of rebleeding, need of hemostatic intervention and mortality. Secondary outcomes were rebleeding, number of blood transfusions received, duration of admission and mortality. Totally 105 patients were included. Of the 49 patients allocated to STAE 31 underwent successful STAE. There was no difference in composite endpoint. Two versus eight patients re-bled in the STAE and control group, respectively. After adjustment for possible imbalances a strong trend was noted between STAE and rate of rebleeding (P = 0.079). The authors concluded that STAE is potentially useful for preventing

R. Loffroy et al. rebleeding in high-risk peptic ulcer bleeding. STAE can safely be performed in selected cases with high risk of rebleeding. Further studies are needed in order to confirm these findings.

Conclusion Massive bleeding from the upper tract remains a challenge. A multidisciplinary team of skilled endoscopists, intensive care specialists, experienced upper gastrointestinal surgeons, and interventional radiologists all have a role to play. The past three decades have seen enormous advances in endovascular device development and treatment of a wide variety of hemorrhagic conditions. The safety and efficacy of TAE for the treatment of life-threatening acute nonvariceal UGIB is now widely accepted and is considered the gold standard for endoscopy-refractory patients. Take-home messages • Gastroduodenal peptic ulcer disease is the most common cause of acute nonvariceal upper gastrointestinal bleeding. • Transcatheter arterial embolization has become the first-line treatment when endoscopic treatment fails to control acute arterial bleeding from the upper gastrointestinal tract. • Cyanoacrylate glue should probably be used more often in such a setting, especially in patients with coagulopathy, because it provides a better and faster hemostasis and does not cause ischemia in welltrained hands. • Most groups have adopted a policy to perform blind embolization on the basis of endoscopic findings in situations that no extravasation is seen angiographically. • Every effort should be made to correct coagulopathy before, during, and after intervention because clinical predictors among of rebleeding, coagulopathy has been shown to adversely affect the success rate for embolotherapy. • Transcatheter arterial embolization is potentially useful even for preventing rebleeding in high-risk peptic ulcer bleeding.

Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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