Looking at the surface of the gastrointestinal (GI)

Imaging and Advanced Technology Nonvariceal Upper Gastrointestinal Hemorrhage: Probing Beneath the Surface RICHARD C.K. WONG Division of Gastroenterology and Liver Disease, Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio Looking at the surface of the gastrointestinal (GI) tract has long been the foundation of practice in GI endoscopy. Indeed, many of our day-to-day management decisions are based largely on what the surface looks like, yet it is generally accepted that visual appearances alone can be quite subjective. For many decades, visual stigmata of recent hemorrhage (SRH) formed the basis from which the endoscopist decided whether or not to perform endoscopic hemostasis in patients with nonvariceal upper GI hemorrhage (NVUGIH). The so-called Forrest classification of SRH in peptic ulcer bleeding was published almost 4 decades ago. 1 Current recommendations for endoscopic therapy in acute peptic ulcer hemorrhage reside entirely on the surface appearance of the bleeding ulcer. 2,3 However, published evidence shows that there is significant interobserver variability in the identification of such SRH. When endoscopists were shown images or videoclips of bleeding peptic ulcers and asked to identify SRH, there was disagreement 25% of the time. 4 Moreover, even among international experts, good agreement could only be reached when there was spurting blood. 5 Furthermore, some published studies have shown that high-risk stigmata, such as a nonbleeding visible vessel (NBVV), may have uncharacteristic visual appearances (nonpigmented, pale, translucent, or pearl-colored protuberance) and thus may be misinterpreted by the endoscopist as low-risk stigmata. 6,7 As Michael V. Sivak, Jr, MD, succinctly noted, It is well-established that visual assessment alone of an ulcer in a patient with upper GI bleeding is inaccurate, especially with respect to ulcers with SRH. Consequently, the use of the Forrest classification as a guide to the need for endoscopic therapy is necessarily inaccurate (personal communication, 2006). Indeed, misguided application of endoscopic therapy (either under- or overuse) can potentially lead to undesired patient outcomes and to inappropriate use of health care resources. Conceptually, it may be more important to know whether a bleeding lesion still has active blood flow or whether such blood flow has ceased, for instance, as a result of spontaneous intravascular thrombosis. Thus, Figure 1. Illustration of a bleeding peptic ulcer with a NBVV undergoing Doppler ultrasound (DopUS) examination using an endoscopic Doppler ultrasound probe that was passed via the accessory channel of a standard endoscope (from reference 11; reprinted with permission). for any particular bleeding lesion that has stopped bleeding, the risk of recurrent bleeding would theoretically be reduced if active blood flow to the bleeding point had ceased. This theoretical concept has led to the development of novel imaging and nonimaging technologies to try and determine whether blood flow is present or absent beneath a bleeding lesion such as a peptic ulcer. Some of these new technologies may also allow for an assessment of certain physical characteristics of subsurface blood flow, such as relative velocity, and may provide information on anatomic and structural aspects of the surrounding tissue in relation to the bleeding lesion. This 2009 Published by Elsevier Inc. on behalf of AGA Institute. 0016-5085/09/$36.00 doi:10.1053/j.gastro.2009.10.018 GASTROENTEROLOGY 2009;137:1897 1911

Figure 2. (A) Endoscopic image of a DopUS probe on a bleeding duodenal ulcer with a NBVV: Doppler-positive. (B) Visual graphic display of the corresponding positive DopUS signal (y axis: frequency shift [khz]; x axis: time [s]). (C) Endoscopic image of the same ulcer after combination endoscopic therapy with epinephrine injection and heat probe: Doppler-negative. (D) Visual graphic display of the corresponding negative DopUS signal (from reference 12; reprinted with permission). review discusses some of these new endoscopic technologies such as the endoscopic Doppler ultrasound (DopUS) probe, endoscopic ultrasound (EUS), and color Doppler-optical coherence tomography (CD-OCT). DopUS DopUS technology is a non-eus (in the traditional sense), nonimaging technique originally developed in England in the early 1980s for the evaluation of bleeding lesions in the GI tract. What is new is the recent heightened interest in the use of this technology in the evaluation of nonvariceal and variceal bleeding lesions in the GI tract. 8 10 Two DopUS systems have been utilized in published studies within the past 6 years: Endo-Dop (DWL GmbH, Singen, Germany) and VTI Endoscopic Doppler System (Vascular Technology Inc, Nashua, NH); however, only the VTI system has received US Food and Drug Administration clearance for use in GI endoscopy in the United States. Current DopUS technology uses a small, flexible, pulsed-wave, 16- or 20-MHz DopUS probe that is passed down the accessory channel of a standard diagnostic (or therapeutic) forward-viewing (or side-viewing) endoscope to make direct physical contact with the lesion of interest, for example, the base of an ulcer. 11 The ultrasound beam exits the distal tip of the probe in linear fashion. 1898

Table 1. Correlation of Endoscopic Appearance of Peptic or Anastomotic Ulcers With DopUS Signal Endoscopic appearance n Doppler ( ), % Active bleeding (spurting) 4 100 Active bleeding (oozing) 5 60 Nonbleeding visible vessel 9 44 Adherent clot 7 14 Flat pigmented spot 11 9 Clean base 19 11 NOTE. Table adapted from reference 13. Various preset scanning depths ranging from less than a millimeter to several millimeters can be selected based on the subsurface blood vessel of interest. For evaluating bleeding peptic ulcers, published studies have utilized a shallow scanning depth of 1.5 mm. The DopUS probe is used to examine the lesion of interest for subsurface blood flow (Figures 1 and 2); this was the subject of a published review. 12 The output signal from the DopUS system is based on the Doppler effect, in which blood cells contained within the subsurface blood vessel act as moving targets reflecting ultrasound waves back to a stationary transducer (DopUS probe). The resultant Doppler shift is automatically calculated by the system and the output (or result) is immediately expressed (in real time) either as an audible Doppler signal (VTI system) or audible plus graphic Doppler signals (DWL system). The Doppler shift equation is: with a significantly lower rate of recurrent bleeding at 30 days than standard management based on visual SRH alone (5.5% vs 29.7%; P.05). The study cohort consisted of patients with severe peptic ulcer hemorrhage from high-risk SRH (spurting bleeding, NBVV, adherent clot). In the study, the end point of Doppler-guided hemostasis was converting a Doppler-positive signal to a Doppler-negative one. Two prospective randomized controlled trials using DopUS technology in NVUGIH are currently enrolling patients in Hong Kong and in the United States. EUS EUS is distinct from DopUS in that it is an imaging technology that can potentially visualize subsurface blood vessels; provide anatomic information about the bleeding lesion, surrounding tissue, and organs; and potentially allow for image-guided hemostasis. A recent study from Levy et al 14 has suggested a possible use of EUS-guided endoscopic hemostasis in selected patients with GI bleeding, which has failed conventional management. In this study of 5 patients with refractory GI bleeding owing to various etiologies (duodenal ulcer, duodenal Dieulafoy lesion, pancreatic pseudoaneurysm, 2 fvcos f d c where f d Doppler frequency shift (Hz); f input ultrasound frequency (Hz); v velocity of moving blood (meters/second); cos cosine of angle ( ) between the ultrasound beam and the axis of blood flow; and c velocity of ultrasound in media (in meters per second). The DopUS instrument allows the endoscopist to differentiate between arterial and venous blood flow (based on the Doppler signal), to estimate depth of the subsurface blood vessel (based on preset scanning depths), and to estimate location of the subsurface blood vessel (based on location of the DopUS probe on the lesion). Published studies using DopUS in acute peptic ulcer hemorrhage have demonstrated the following. (1) Ulcers that are Doppler-positive are significantly more likely to experience recurrent bleeding than Doppler-negative ulcers. (2) Ulcers that remain Doppler-positive immediately after endoscopic therapy are at significantly higher risk of recurrent bleeding. 13 (3) Positive correlation exists between endoscopic SRH and Doppler signal (Table 1). In a recent, prospective, nonrandomized, cohort study (published in abstract form), Jensen et al 8 demonstrated that Doppler-guided endoscopic therapy was associated Figure 3. Forward-view type ultrasonic endoscope (from reference 15; reprinted with permission). 1899

Figure 4. A, EDOCT scanner attached over the accessory port of the endoscope. B, Endoscope tip with catheter passed through the accessory channel. C, Fiber-optic probe within the transparent plastic catheter (outer diameter 2 mm). The imaging tip consists of an optical fiber (O) terminated with a focusing lens (L) and a 90 prism (P) to divert the light beam sideways. The catheter was sealed with adhesive (A), D, Videogastroscope image of the catheter in contact with the stomach wall of a GAVE patient (from reference 20; reprinted with permission). GI stromal tumor), standard mechanical radial and electronic curved linear array echoendoscopes were used. EUS-guided therapy was successful in all 5 cases and consisted of injection of alcohol or cyanoacrylate using a standard curved linear array echoendoscope. Standard echoendoscopes are oblique-viewing and as such it is not possible to simultaneously visualize the lesion of interest by endoscopy and by ultrasound. A new prototype forward-viewing therapeutic echoendoscope has become available in which both the endoscopic and ultrasound views are orientated in a forward direction. Endoscopic accessories exit the working channel of the echoendoscope at its distal tip in direct alignment with the axis of the shaft rather than at an oblique angle from the side (Figure 3). This prototype echoendoscope was used by Voermans et al 15 in 7 patients to successfully perform transmural endoscopic drainage of pancreatic pseudocysts. A recent preliminary study from our institution, using the prototype forward-viewing therapeutic echoendoscope, demonstrated that EUS-guided thermalcontact therapy could be performed in a porcine arterial bleeding model. 16 However, EUS-guided injection therapy could not be accomplished owing to loss of acoustic coupling as the injection needle was advanced into the gastric wall. Although preliminary experience suggest that EUSdirected endoscopic hemostasis may be feasible in selected patients, major obstacles remain, including training, cost, and the portability of such systems, as well as technical issues such as acoustic coupling, imaging artifacts from retained intraluminal blood, and the ability to endoscopically visualize the bleeding lesion at the same time as performing EUS-guided hemostasis. In this regard, optical forward-viewing instruments may have a theoretical advantage over standard oblique-viewing instruments because it may permit direct endoscopic visualization of the lesion at the same time as EUS imaging. Finally, it is also uncertain whether current EUS imaging has sufficient resolution to reliably detect blood flow in subsurface vessels associated with bleeding peptic ulcers, which, in a seminal study on recurrently bleeding gastric ulcers (Swain et al 17 ), the bleeding ulcer had a mean external diameter of 0.7 mm (range 0.1 1.8 mm). CD-OCT OCT is a technique that utilizes tissue reflectivity of near-infrared light to provide high-resolution, crosssectional tissue imaging. 18 When the tissue consists of moving particles, such as blood cells, the reflected light undergoes a Doppler frequency shift. High-resolution optical flow imaging is then achieved by measuring this frequency in OCT, in a similar manner to DopUS. CD- OCT (also called endoscopic Doppler OCT [EDOCT]) is an advanced technology that is able to image subsurface blood flow as well as provide structural tissue information. One of the technical limitations of OCT is its shallow depth of view (generally 1.5 mm). A study from our group using an in vivo animal model demonstrated that CD-OCT could provide high-resolu- 1900

Figure 5. A and B, Color EDOCT images of GAVE in two patients. C, Consistent with the H&E staining, dilated microvasculature (arrows) is present immediately beneath the tissue surface. D, Consistent with the CD34 staining, dilated microvasculature (arrows) is present immediately beneath the tissue surface (C and D, Orig. mag. X 10) (from reference 20; reprinted with permission). tion, cross-sectional flow imaging of subsurface blood vessels before and after the application of certain local hemostatic interventions such as injection of epinephrine or sclerosant, thermal-contact therapy, and laser photocoagulation. 19 Using a prototype clinical CD-OCT system (Figure 4), Yang et al 20 subsequently published the first clinical feasibility study of CD-OCT in the human GI tract in normal and disease states such as gastric antral vascular ectasia (GAVE) (Figure 5). Conclusion and Future Direction In the management of patients with NVUGIH, the introduction of novel advanced technologies has gradually shifted the focus away from looking at visual surface stigmata to an assessment of subsurface blood flow. Being able to determine the presence or absence of blood flow beneath a bleeding lesion may allow for subsurface mapping of blood flow and may provide the endoscopist with the ability to precisely target and titrate the application of endoscopic therapy based on blood flow. Such information may also allow the endoscopist to risk-stratify uncertain or indeterminate visual stigmata based on subsurface blood flow. Conceptually, this represents a paradigm shift in the management approach to NVUGIH as the starting points and end points of endoscopic therapy will then be based on knowledge of subsurface blood flow rather than to visual surface stigmata alone. Only then will we be really probing beneath the surface. References 1. Forrest JAH, Finlayson NDC, Shearman DJC, Endoscopy in gastrointestinal bleeding. Lancet 1974;II:394 397. 2. Gralnek IM, Barkun AN, Bardou M. Management of acute bleeding from a peptic ulcer. N Engl J Med 2008;359:928 937. 3. NIH Consensus Conference. Therapeutic endoscopy and bleeding ulcers. JAMA 1989;262:1369 1372. 4. Laine L, Freeman M, Cohen H. Lack of uniformity in evaluation of endoscopic prognostic features of bleeding ulcers. Gastrointest Endosc 1994;40:411 417. 5. Lau JYW, Sung JJY, Chan ACW, et al. Stigmata of hemorrhage in bleeding peptic ulcers: an interobserver agreement study among international experts. Gastrointest Endosc 1997;46:33 36. 6. Freeman ML, Cass OW, Peine CJ, et al. The non-bleeding visible vessel versus sentinel clot: natural history and risk of rebleeding. Gastrointest Endosc 1993;39:359 366. 7. Chen JJ, Changchien CS, Lin CC, et al. The visible vessel on the bleeding gastric ulcer: an endoscopic-pathological study. Endoscopy 1997;29:821 826. 8. Jensen DM, Ohning GV, Singh B, et al. For severe UGI hemorrhage Doppler ultrasound probe is more accurate for risk stratification and helpful for complete endoscopic hemostasis than lesion stigmata alone [abstract]. Gastrointest Endosc 2008;67: AB81 (abs.#264). 9. Wong RCK, Farooq FT, Chak A. Use of a new endoscopic Doppler ultrasound probe for the identification of gastric varices. Gastrointest Endosc 2007;65:491 496. 1901

10. Battaglia G, Bocus P, Morbin T, et al. Endoscopic Doppler USguided injection therapy for gastric varices: case report. Gastrointest Endosc 2003;57:608 611. 11. Wong RCK. Risk stratification of nonvariceal UGI hemorrhage for the practicing endoscopist. Tech Gastrointest Endosc 2005;7: 118 123. 12. Wong RCK. Endoscopic Doppler US probe for acute peptic ulcer hemorrhage [review]. Gastrointest Endosc 2004;60:804 812. 13. Wong RCK, Chak A, Kobayashi K, et al. Role of Doppler US in acute peptic ulcer hemorrhage: can it predict failure of endoscopic therapy? Gastrointest Endosc 2000;52:315 321. 14. Levy MJ, Wong Kee Song LM, Farnell MB, et al. Endoscopic ultrasound (EUS)-guided angiotherapy of refractory gastrointestinal bleeding. Am J Gastroenterol 2008;103:352 359. 15. Voermans RP, Eisendrath P, Bruno MJ, et al. Initial evaluation of a novel prototype forward-viewing US endoscope in transmural drainage of pancreatic pseudocysts. Gastrointest Endosc 2007; 66:1013 1017. 16. Pollack MJ, Elmunzer BJ, Trunzo JA, et al. Initial evaluation of a novel prototype forward-viewing echoendoscope in a porcine arterial bleeding model [abstract]. Gastrointest Endosc 2008;67: AB81 (abs.#265). 17. Swain CP, Storey DW, Bown SG, et al. Nature of the bleeding vessel in recurrently bleeding gastric ulcers. Gastroenterology 1986;90:595 608. 18. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science 1991;254:1178 1181. 19. Wong RCK, Yazdanfar S, Izatt JA, et al. Visualization of subsurface blood vessels by color Doppler optical coherence tomography in rats: before and after hemostatic therapy. Gastrointest Endosc 2002;55:88 95. 20. Yang VXD, Tang S-J, Gordon ML, et al. Endoscopic Doppler optical coherence tomography in the human GI tract: initial experience. Gastrointest Endosc 2005;61:879 890. Reprint requests Address reprint requests to: Richard C.K. Wong, MD, Division of Gastroenterology and Liver Disease (Wearn 247A), University Hospitals Case Medical Center, 11100 Euclid Avenue, Cleveland, Ohio 44106-5066. e-mail: richard.wong@uhhospitals.org. Conflicts of interest The author discloses the following: Vascular Technology, Inc. (research funding); GE Global Research (consultant). 1902