Ectopic Variceal Bleeding

Patients with portal hypertension can develop ectopic varices, which occur most commonly around surgical stomas, duodenum, jejuno-ileum, and colon [30]. While rare, rates of bleeding from ectopic varices account for up to 5% of all variceal bleeding. Ectopic varices have a fourfold increased risk of bleeding compared to esophageal varices, and mortality rates have been reported up to 40% [31, 32].

Duodenal varices may be managed in a similar way to esophageal and gastric varices. One large review highlighted the use of TIPS, BRTO, band ligation, and sclerotherapy in these patients [33]. There are a few reports of successful obliteration of duodenal varices using EUS-guided coil placement with or without cyanoacrylate injection [34–36]. An additional report successfully obliterated a duodenal varix using EUS-guided thrombin injection [37].

Rectal varices arise from portosystemic collaterals that occur as a result of portal hypertension. These varices are commonly diagnosed on anoscopy [38]. The single largest study of rectal varices identified 96 cirrhotic patients, of which 51% had evidence of rectal varices on EUS [39]. Interestingly, only half of the patients identified on EUS to have varices actually had endoscopic evidence of varices. Massive bleeding from rectal varices has been reported in 0.5–3.6% of cases [40–42]. Sharma et al described a series of 5 patients with lower GI bleeding, 2 of whom required EUS to identify the rectal varices [43]. Several other groups have reported EUS-guided coiling and/or cyanoacrylate injection for rectal varices [44–48]. EUS-guided CYA injection has also been reported for use in the management of peristomal varices [49].

Nonvariceal Gastrointestinal Bleeding

Despite initial resuscitation, medical management, and endoscopic therapy, certain patients will have recurrent bleeding requiring additional interventions [50]. Endoscopic therapy for nonvariceal gastrointestinal bleeding may include one or a combination of the following: epinephrine injection, thermal coaptive therapy, clipping, and more recently hemostatic powders [51, 52]. Upon failing endoscopic therapy, the current standard of care would include either transcatheter arterial embolization (by interventional radiology) or surgical intervention. Ultrasound-guided techniques have allowed for some novel treatments for patients with nonvariceal gastrointestinal bleeding.

A Doppler endoscopic probe has been used to help characterize peptic ulcer rebleeding risk when compared to conventional measures such as the Forrest classification. While certain studies have shown no added benefit of the Doppler probe in the management of patients with ulcer-related bleeding [53, 54], one prospective study of 163 patients showed that the Doppler probe accurately predicted rebleeding rates based upon arterial blood flow at the base of the ulcer [55]. Importantly, the Doppler flow measured after endoscopic treatment correlated with rebleeding risk. This study was the first to highlight the role of Doppler in addition to the Forrest classification to determine a more accurate endpoint for endoscopic treatment. Future multicenter randomized controlled studies are needed to confirm these findings.

Endoscopic ultrasound–guided imaging has allowed for more precise interventions in the management of nonvariceal gastrointestinal bleeding. Fockens et al. were the first group to use a radial echoendoscope to aid in the management of 3 patients with Dieulafoy lesions [56]. Using EUS, they located a submucosal blood vessel, which was then injected with epinephrine/polidocanol as sclerotherapy.

Another reported case series used a curved linear echoendoscope to manage five patients with refractory gastrointestinal bleeding from GI stromal tumors, hemosuccus pancreaticus, and a duodenal ulcer [57]. These five patients had failed multiple prior endoscopic interventions requiring multiple transfusions. Each patient underwent a careful EUS examination to identify the culprit vessel, which was then injected with either alcohol or cyanoacrylate glue via a 22-gauge FNA needle. Postinjection imaging confirmed a lack of flow within the culprit vessel. Over a mean follow-up of 1-year, there were no complications or rebleeding events. A similar case series reported five patients with refractory GI bleeding secondary to a gastroduodenal artery aneurysm, fundal aneurysm, or Dieulafoy lesion. Using EUS guidance, the bleeding vessel was punctured with a 19-gauge FNA needle and injected with either cyanoacrylate glue or polidocanol. Over a mean follow-up of 9-months, only one patient rebled, requiring repeat EUS-guided injection. Several other case reports have used EUS-guided sclerotherapy to treat a variety of patients with bleeding from Dieulafoy’s lesions [58, 59], a GIST [60], a splenic pseudoaneurysm after pseudocyst drainage [61], and arterial pseudoaneurysm s [62–64].

Law et al. examined the safety and efficacy of EUS-guided management of nonvariceal GI bleeding in 17 patients with refractory GI bleeding [65]. These patients included those with bleeding GIST, colorectal vascular malformations, duodenal masses or polyps, Dieulafoy lesions, peptic ulcers, rectally invasive prostate cancer, pseudoaneurysms, ulcerated esophageal cancer, and ulcer after Roux-en-Y gastric bypass. These patients had either failed endoscopic or radiologic procedures, or were not candidates for surgical intervention. Many of the patients had received multiple blood transfusions, failed multiple endoscopic attempts, and some even failed IR-guided interventions or surgical intervention. Various EUS-guided procedures were performed including sclerotherapy injection, coil embolization, and even band ligation, whereby EUS was used to create a subepithelial tattoo mark at the location of the vessel. After endoscopic treatment, Doppler confirmed eradication of the underlying blood vessel. Over a median follow-up of 1-year, only two patients had recurrent bleeding. One patient rebled 3 years later and required an additional EUS-guided intervention. Another patient with invasive prostate cancer continued to bleed despite endoscopic therapy.

While current international guidelines do not endorse a role for either Doppler assessment or EUS-guided therapy of nonvariceal GI bleeding [51, 52, 66], there are several case reports that suggest such treatments are both safe and effective for managing certain patients with refractory bleeding. Being able to target the culprit vessel directly and confirm complete eradication after endoscopic therapy may assist in the management of certain patients presenting with nonvariceal GI bleeding.

Pancreatic Pseudoaneurysms

Pancreatic pseudoaneurysms are a rare complication of pseudocyst formation in the context of chronic pancreatitis [67]. These pseudoaneurysms can result in life-threatening bleeding, especially in the context of EUS-guided cyst drainage [68]. While traditionally performed by IR-guided embolization [69], or surgery in severe circumstances [70], there is emerging data of an EUS-guided approach. There are several reports of successful treatment of pseudoaneurysms using a combination of EUS-guided coiling, thrombin injection, and glue injection [71–74].

Portal Pressure Gradient Measurement

Diagnosing and measuring portal hypertension is important in classifying and prognosticating patients with cirrhosis [75, 76]. Transcutaneous portal venography and pressure measurements are not performed in clinical practice due to technical difficulties and a high rate of complications [77]. The portal pressure gradient (PPG) can be measured as the difference between the portal vein pressure and the pressure within the hepatic vein. The most common approach to measuring portal pressure is the transjugular route by interventional radiologists [78]. In this approach, a catheter is placed into the jugular vein and advanced into the right hepatic vein under fluoroscopic guidance. Next, the hepatic vein pressure gradient (HVPG) is calculated by subtracting the free hepatic venous pressure from the wedged hepatic venous pressure [79]. A HVPG >5 mmHg is consistent with portal hypertension, while a HVPG >10 mmHg is consistent with clinically significant portal hypertension [80].

Lai and colleagues were the first to report EUS-guided portal vein pressure measurement in an animal study [81]. In a cohort of 21 pigs, a PH model was generated in 14 using polyvinyl alcohol injection and a coagulopathy model generated in 7 with heparin administration. The transduodenal approach was used to access the portal vein in 21 pigs with a 22G FNA needle and a transabdominal ultrasound (TAUS)-guided transhepatic approach in 14 of 21 pigs via a 22-gauge needle. PVP measurements were obtained in 18 of 21 swine. Minor complications found at necropsy included small subserosal hematomas at the EUS puncture site in all 21 pigs and a 25 mL blood collection between the liver and duodenum in 1 of 7 anticoagulated pigs. Failure to measure pressures in 3 subjects may have occurred due to thrombosis within the FNA needle. There was a strong correlation between EUS- and transhepatic-measured PVP (r = 0.91).

In 2007, Giday and colleagues used the transgastric approach with a 19G needle and modified ERCP catheter to obtain continuous PVP measurement without an echoendoscope in place [82]. Five pigs were successfully catheterized, and no hemorrhage or liver injury was noted on necropsy on all subjects despite use of a significantly larger caliber needle. Two of five pigs survived for 2 weeks and exhibited no signs of adverse events prior to and after necropsy. In 2008, the same group used the same methods to measure fluctuations in PVP and inferior vena cava (IVC) pressures in pigs that underwent common endoscopic procedures: esophagogastroduodenoscopy (EGD), colonoscopy, and ERCP. PV and IVC were accessed using a 19G needle and modified ERCP catheter [83]. Access and pressure measurements of both vessels were achieved in all 5 pigs. Necropsy showed no evidence of injury in all subjects. A threefold increase in PVP was noted between baseline and during ERCP. Values of IVC pressure, as well as of PVP for EGD and colonoscopy, were similar between baseline and procedure time.

The first human case of EUS-guided PVP measurement was reported by Fujii-Lau and colleagues in 2014, in which a 22G FNA needle connected to an arterial pressure catheter was used to rule out portal hypertension in a 27-year-old man with arteriovenous malformations secondary to Noonan syndrome [84]. There was no evidence of bleeding or hemodynamic instability after the procedure.

Schulman et al. demonstrated a novel method of measuring PVP using an EUS-guided 22G needle, through which a wire with a digital pressure sensor was passed [85]. Conventional transjugular catheterization was performed as a control. Successful device placement and PVP measurement were achieved in 5 of 5 pigs with no hemorrhage or thrombosis noted on both EUS and postprocedural necropsy. Comparison of EUS-measured PVP with transjugular HVPG measurements showed a difference of within 1 mmHg for all pigs. The study endoscopists rated the procedure as having overall low subjective workload. The authors used the same device to perform PVP measurement in 5 other pigs that were then survived for 14 days before necropsy. PVP was again measured on day 14. No signs of complications were observed during the 2-week survival period, and necropsy again showed no abnormalities. PVP values on day 0 and day 14 were similar for all 5 pigs.

Our group demonstrated that EUS-guided PPG could be performed using a simple manometer setup without a wire [86]. The study was performed on 3 live pigs using a 25-gauge straight needle with a compact manometer. The portal vein, right hepatic vein, inferior vena cava, and aorta were punctured and pressures were measured. Simultaneously, an IR-guided approach was used to measure pressures in the aorta, inferior vena cava, and right hepatic vein (wedged and free). The correlation coefficient was approximately 0.99 between EUS-guided and IR-guided approach. Similar results using slightly different devices have been reported by other groups in animal studies. The transhepatic route, which has been used in these animal studies, is thought to be protective against bleeding due to tamponade of the catheter track by the hepatic parenchyma. Furthermore, Doppler can be used to ensure there is no active bleeding during withdrawal of the needle.

Our group published the first study of EUS PPG measurements in a series of human patients [87]. All procedures were successful in obtaining a portal pressure gradient in 28 patients and there were no complications. The apparatus for PPG measurement includes a linear echoendoscope, a 25G FNA-needle, noncompressible tubing, a compact digital manometer, and heparinized saline. The tubing is connected by a luer lock to the distal port of the manometer, while the heparinized saline is connected to the proximal port of the manometer. The end of the tubing is connected via a Luer lock to the inlet of the 25G needle. Prior to echoendoscope insertion, the manometer is zeroed at the mid-axillary line. The patient remains supine during the EUS procedure, and the manometer is placed at the patient’s mid-axillary line (Fig. 29.2).

The middle hepatic vein is targeted most commonly due to its larger caliber and better alignment with the needle trajectory on linear EUS (Fig. 29.3). Doppler flow is used to confirm the typical multiphasic waveform of hepatic venous flow. Using the 25G FNA needle, a transgastric transhepatic approach is used to puncture the hepatic vein. Approximately 1 cc of heparinized saline is used to flush the needle, which is visible on EUS, confirming good position within the vessel. Following the flush, the pressure reading on the manometer will immediately rise, fall, and equilibrate at a steady pressure, which is recorded. Repeat flushing and measurement is performed three times to ensure accuracy, and a mean hepatic vein pressure is recorded. The FNA needle is slowly withdrawn back into the needle sheath with Doppler flow to ensure there is no flow within the needle tract. If flow is noted within the needle track, the needle is kept in place to allow for tamponade and reduce risk of bleeding.

Next, the umbilical portion of the left portal vein is targeted (Fig. 29.4). Doppler flow is used to confirm the typical venous hum of portal venous flow. Using the 25G FNA needle, a transgastric transhepatic approach is used to puncture the portal vein. Three subsequent flushes and measurements are taken as above, which provides a mean portal vein pressure.

The portal pressure gradient is calculated by subtracting the mean portal vein pressure from the mean hepatic vein pressure. The patient is recovered in a similar manner to a routine diagnostic EUS with FNA. Postprocedural antibiotics are given for 5 days post procedure.

See Video 29.1 depicting a live case where PPG was measured in a human patient. The PPG measurement correlated well to clinical and endoscopic parameters of cirrhosis including the presence of esophageal varices and portal hypertensive gastropathy. In a related study, our group showed the safety of combining EUS-guided liver biopsy and EUS PPG during the same endoscopy session [88]. These studies suggest that EUS-guided PPG measurements are both feasible and safe in cirrhotic patients. Furthermore, measuring portal pressure directly, as opposed to the commonly used HVPG provided by transjugular approach, may provide more accurate measurements, especially in the setting of presinusoidal portal hypertension.

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

TIPS involves the creation of a low-resistance connection between the hepatic vein and intrahepatic portal vein using an expandable metal stent under angiographic and radiologic guidance. TIPS is indicated in patients with refractory ascites, variceal bleeding, and may be considered in patients with hepatorenal syndrome [89–92]. The first EUS-guided placement of an intrahepatic portosystemic shunt was performed in a live porcine model [93]. Under EUS-guidance, a 19-gauge FNA needle was passed through the hepatic vein into the portal vein, and after contrast confirmed adequate needle placement, a metal stent was placed over a 0.035-inch guidewire that bridged the hepatic and portal veins. The procedure was performed in 2 separate live pigs, and during 2-week follow-up, there were no complications. Two other groups utilized a similar procedural technique using instead a fully covered lumen-apposing metal stent (LAMS) to minimize the risk of possible stent migration. Both of these subsequent studies were performed in porcine models with no apparent complications [85, 94].

A recent editorial, however, highlights the danger of immediately concluding that EUS-guided placement of an intrahepatic is both safe and effective [95]. First, the procedure may be associated with a higher risk of bleeding when performed in cirrhotic patients with elevated portal pressures and poor coagulation. Second, there may be a higher risk of infection compared to traditionally placed TIPS due to the transgastric puncture. Third, a key component of TIPS is to choose the correct hepatic vein so as to minimize the angulation of the stent. Lastly, since the risks of TIPS are fairly low already, it is unclear whether EUS-guided procedure would have any significant benefits.

Intravascular Thrombi and Venous Sampling

Portal vein thrombosis may occur in the context of cirrhosis, hepatocellular carcinoma, pancreaticobiliary malignancy, and hematologic disorders including thrombophilias [96–98]. Staging of hepatocellular carcinoma and pancreaticobiliary malignancies rely on the accurate differentiation of a tumor thrombus from a benign portal vein thrombus [99–102]. Although contrast-enhanced ultrasound, CT, and MR have been shown to be helpful, occasionally imaging is nondiagnostic. In certain cases, targeted biopsies of the portal vein may be helpful for staging. Several reports have shown that EUS-guided FNA of a portal vein thrombus is both safe and helpful in differentiating a benign from a malignant thrombus. Importantly, FNA of the extrahepatic portal vein can be performed using a transduodenal approach, thus avoiding any liver tissue. EUS-guided FNA has also been useful in sampling a splenic artery thrombus, pulmonary artery thrombus, and an IVC thrombus in suspected hepatocellular carcinoma, lung cancer, and adrenal cancer, respectively [103–105].

One study examined the role of EUS-guided FNA of remote malignant thrombi in a retrospective cohort of 17 patients [106]. Of these patients, 12/17 (70.5%) patients had positive cytology. Most importantly, of the 8 patients with pancreatic cancer, 2/8 (25%) patients who were previously deemed resectable were now considered unresectable. Other studies have confirmed this finding, noting that circulating tumor cells in the context of pancreaticobiliary malignancy are found more frequently from portal vein blood than peripheral blood [107, 108].

Access to the Heart

Given the proximity of the esophagus to the heart and the widespread use of transesophageal echocardiography, some endoscopists have postulated a possible role for EUS-guided therapies of the heart. Fritscher-Ravens et al performed the first reported EUS-guided puncture of the heart using 19-gauge and 22-gauge needles [109]. Using this technique, they were able to access the left atrium, left ventricle, coronary arteries, and aortic valve. In the study, they successfully injected contrast agents, sampled pericardial fluid, biopsied a left atrial mass, performed radio-frequency ablation of the aortic valve, and inserted pacing wires. There were no complications during the procedures. There are 3 reports of EUS-guided cardiac access performed in human patients. One group described an EUS-guided drainage of a pericardial cyst [110], while two other groups described FNA of a pericardial tumor [111], and FNA of a right atrial tumor [112]. All three of these procedures had no significant adverse events.

Chemotherapeutics

Systemic chemotherapy is the mainstay of treatment for many types of cancer and is commonly associated with dose-limiting side effects. Furthermore, certain patients may not be candidates for systemic chemotherapy due to underlying comorbidities. Newer techniques, including transarterial chemoembolization (TACE), have provided certain patients with alternatives to traditional chemotherapy or surgical resection [113, 114]. TACE allows for microbead injection into the hepatic artery and affords higher hepatic drug levels with lower systemic levels, but major risks include decompensation of underlying liver disease and ischemic biliary strictures, since the hepatic artery is the sole provider of biliary duct blood supply [115, 116]. Newer techniques have attempted to inject chemotherapy in the portal vein in order to reduce the risk of ischemic biliary strictures. EUS-guided portal vein injection of chemotherapy (EPIC) has been performed successfully in animal models [117, 118]. EPIC allows for placement of drug-eluting microbeads or nanoparticles that results in lower systemic drug levels, but higher liver drug levels when compared to systemic injection. No direct comparisons between EPIC and TACE have been performed. Emerging evidence has suggested a role of direct portal vein injection of iodine-125 seeds into patients with HCC complicated by portal vein tumor thrombosis [119]. While these procedures were performed under CT guidance and results were promising, an EUS-guided approach may be equally efficacious and perhaps safer.

The Future of EUS-Guided Vascular Therapy

EUS-guided vascular procedures are an exciting field that bridges gastroenterology with interventional radiology. As equipment and techniques continue to develop, it is likely that more patients will be able to benefit from these less-invasive procedures. Given the specialized equipment and expertise required to perform many of these procedures, they will likely continue to be confined to high-volume tertiary care centers. Large multicenter prospective randomized controlled trials, which compare EUS-guided procedures with the current standard of care, are required to better delineate the effectiveness and safety of these procedures. While many of the procedures outlined in this chapter are innovative and exciting, few have been able to prove clinical benefit above and beyond the current standards of care.

Conclusion

EUS-guided vascular interventions are a promising new field that requires high-quality evidence in order to be incorporated into current guidelines. These less-invasive procedures offer alternatives to traditional endoscopy and interventional radiology, especially in patients in whom other options are limited or not feasible.