Gastrointestinal Intervention 2013; 2(2): 73-77
Published online December 30, 2013 https://doi.org/10.1016/j.gii.2013.09.003
Copyright © International Journal of Gastrointestinal Intervention.
Yoon Suk Jung, and Dong Il Park*
Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110 746, South Korea
Correspondence to:*Corresponding author. Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyung-Dong, Jongro-Ku, Seoul 110 746, South Korea.,
Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are the standard treatment modalities for noninvasive gastrointestinal malignancies. To improve their efficacy and safety, endoscopic procedures require the formation of an adequate submucosal cushion, which is made between the lesion and the proper muscle layer. Ideal submucosal injection solutions should have the following characteristics: (1) they provide a long-lasting and high submucosal cushion, (2) are safe and nontoxic, (3) inexpensive, (4) readily available, (5) easy to inject, and (6) they preserve specimen tissue for accurate histopathological lesion assessment. Various submucosal agents have been developed for effective EMR and ESD. These submucosal agents differ with regard to their efficacy, cost, and availability. The appropriate submucosal injection solution should be chosen on a case-by-case basis and should take into consideration the size and location of the lesion and the type and the time of the procedure. Therefore, elucidating the characteristics of various submucosal injection solutions is important for appropriately selecting submucosal injection solutions and for successful endoscopic procedures. In this review article, we provide an overview of the characteristics of different submucosal injection solutions.
Keywords: Endoscopic mucosal resection, Endoscopic submucosal dissection, Gastrointestinal neoplasm, Submucosal injection solution
Endoscopic resection modalities such as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are standard procedures for treating noninvasive mucosal tumors and adenomas, which are precursors to cancer in the gastrointestinal (GI) tract.1–4 To increase their efficacy and safety, EMR and ESD techniques require the injection of a fluid agent underneath the mucosa into the submucosal layer.5 Submucosal injection solutions are used to separate the lesion from the muscularis propria to allow the complete resection of the lesion and to prevent perforation and thermal injury to the GI wall.6 Normal saline (NS) solution is most commonly used in clinical practice because of its low cost and ease of use. However, its use is hampered by the quick absorption of the NS solution into the surrounding tissue, thereby resulting in the need for repeated injections.7 In recent years, various submucosal injection solutions such as hyaluronic acid (HA), glycerol, dextrose water (DW), fibrinogen mixture (FM), and hydroxypropyl methyl-cellulose (HPMC) have been developed and studied for safety and efficacy in EMR and ESD. In addition, there have been encouraging results with using autologous blood as a submucosal injection solution. Table 1 summarizes the characteristics of the various submucosal injection solutions. The appropriate selection of sub-mucosal injection solutions is important for successful EMR and ESD. This review addresses recent advances regarding the development of efficient submucosal injection solutions for use during EMR or ESD. The characteristics of various submucosal injection solutions are also described.
Ideal submucosal injection solutions should provide a long-lasting submucosal cushion and should be safe, inexpensive, readily available, nontoxic, easy to inject, and avoid histopathological tissue damage. They should also provide a sufficiently high submucosal elevation to facilitate an
Much research has been devoted to determining the ideal sub-mucosal injection for endoscopic resection.7 Except for NS solution, most solutions are difficult to administer or prepare, are associated with toxicity, or are expensive. Some solutions have limited human data on their safety and efficacy. Therefore, NS solution is widely used for EMR in most institutions. However, the greatest problem with NS solution is that it rapidly dissipates into the surrounding tissue. As a result, NS solution requires repeated injections, which makes it difficult to produce an adequate submucosal fluid cushion and maintain a sufficient height, especially for flat elevated lesions or large lesions. Normal saline solution appears to be adequate for EMR of non-flat elevated lesions and small lesions.
Hypertonic saline solution is an inexpensive, readily available, easy-to-inject NS-like solution that creates a higher mucosal elevation than NS solution.5 However, tissue damage and local inflammatory reactions have been reported at the injection site of hypertonic sodium chloride (3.75%).9
Hyaluronic acid (HA) is a type of glycosaminoglycan found in connective tissue.6 The current indications for HA in clinical practice in many countries are for intra-articular injections for osteoarthritis and for use in eye surgery.10 In 2007 in Japan, the Japanese National Health Insurance approved HA as an injection solution for EMR.10
The efficacy of HA in mucosal elevation has been previously reported in an animal model.5,10,11 Yoshida et al10 showed that mucosal elevation was greater with HA than with NS in resected and living animal models. Hyun et al11 demonstrated that the mucosal elevation induced by 0.1% HA lasted longer than the elevation by NS or by mannitol in a resected mongrel colon. The efficacy of HA in EMR and ESD has also been reported in clinical practice. Several studies show that HA provides the longest lasting fluid cushion.12–14 Using a 0.4% HA solution enabled sufficient lifting of a colorectal and gastric intramucosal lesion during endoscopic resection, thereby reducing the need for additional injections and the risk of perforation.15,16 Using HA moreover resulted in a greater number of successful
We have recently conducted a randomized, open-label, controlled, multicenter safety and efficacy trial of HA (Endo-Ease Unimed Pharm Inc., Seoul, South Korea). It was used as a submucosal injection solution in the endoscopic resection of gastric neoplasms. Similar to the aforementioned studies, we were able to confirm that HA is superior to NS solution with regard to its higher usefulness rate [33/37 (HA) vs. 21/36 (NA);
Hyaluronic acid is the one of the most ideal agents for submucosal injections, although it has several shortcomings. First, HA is expensive and has limited availability. Second, HA is very viscous and must be diluted to facilitate injection. Viscosity because of high concentrations of HA may make snaring difficult.10 Third, HA used for EMR and ESD may stimulate the growth of residual tumor cells. Matsui et al19 demonstrated that HA enhances tumor growth and CD44 expression of cancer cells at the wound sites. Therefore, HA should not be used for endoscopic piecemeal resection procedures because it increases the risk of residual tumors. Hyaluronic acid appears to be an adequate agent for ESD [particularly for the curative treatment of early gastric cancer (EGC) or early colorectal cancer (ECC)] because of its higher
Fujishiro and colleagues20 evaluated the possibility of developing an appropriate low-cost HA solution by diversifying its molecular weight and mixing it with various solutions such as glycerol or DW. They report that a mixture of high-molecular-weight HA and glycerol resulted in excellent outcomes for ESD of gastrointestinal tumors.21 Glycerol (which contains glycerin and fructose) was the better mixing solution for HA, compared to pure NS solution, because glycerin produces hypertonic potency over extracellular fluid without tissue damage and fructose increases the viscoelasticity of the HA solution because of its cross-linking of HA molecules.21
Glycerol (glycerol, Chugai Pharmaceutical Co., Tokyo, Japan) is a hypertonic solution consisting of 10% glycerin and 5% fructose in a NS solution.6 It has been widely used as an osmotic agent against cerebral edema and has no toxic systemic effects.22 In 1995, glycerol was first introduced as a submucosal injection solution in a report of 24 patients with EGC who were treated by the endoscopic aspiration mucosectomy method.23 Since then, a few studies have evaluated its effect as a submucosal injection solution. Uraoka et al24 compared the efficacy of using glycerol or using NS as the injecting solution for EMR of colorectal laterally spreading tumors (LSTs). They showed that the
Dextrose water (DW) is a hypertonic solution that produces and maintains a higher and more prolonged mucosal elevation, compared to NS solution.25,26 Dextrose water is furthermore an inexpensive and easily available solution. Varadarajulu et al25 showed that 50% DW is superior to NS as a submucosal fluid cushion because it allows a better
In 2004, Lee et al28 investigated the clinical outcome of EMR with a submucosal injection of fibrinogen mixture (FM). Lee et al28 confirmed two significant characteristics of FM: (1) its viscosity produces a long-lasting submucosal elevation that allows EMR to be performed more easily without the need of additional injections, and (2) it has a microvascular hemostatic effect, thereby keeping the visual field clear. The authors subsequently conducted a prospective randomized study comparing the efficacy of FM with that of the NS solution.29 A total of 72 patients with EGC were randomly assigned to receive EMR with submucosal injections of either NS or FM. The authors reported that the mean procedure time, the mean submucosal injection volume, and the need for additional submucosal injections were lower in the FM group than in the NS group, although no significant differences were observed between the two groups in the rates of
Hydroxypropyl methylcellulose (HPMC), a cellulose derivative with viscoelastic properties, is primarily used by ophthalmologists in Western countries for creating artificial tears.6,30 Feitoza et al31 conducted a preliminary study regarding the efficacy of HPMC. They demonstrated that HPMC creates a long-lasting submucosal fluid cushion with minimal tissue reaction.31 Feitoza in a subsequent study successfully performed a novel EMR technique by using HPMC for removing large areas of the mucosa in a porcine model.32 A Korean study reveals that the mucosal elevation lasted longer with 0.1% HA, 0.3% HPMC, and 2% FM than with 0.9% NaCl or 20% mannitol, and that the duration of the mucosal elevation was correlated with viscosity, but not with osmolarity.11 Lenz et al33 in a recent study showed that in the porcine stomach, the length of the HPMC submucosal fluid cushion is longer than what can be achieved with NS solution.
Hydroxypropyl methylcellulose and HA are very viscous and must be diluted to facilitate injection.7 Hydroxypropyl methylcellulose is less expensive than HA [0.83% HPMC as a generic product costs US $0.15/mL in the United States (approximately ₩160.85/mL in Korea)].6 However, HPMC is a synthetic product that may give rise to antigenic reactions, whereas HA exists in the connective tissue of mammals and is not antigenic.6 Furthermore HPMC toxicity testing in animal models is required for clinical applications in patients.
Several studies have recently reported encouraging results when autologous blood is used for submucosal injection.34–36 Giday et al34 evaluated six solutions as cushioning agents in live pigs: 5 mL of NS; NS plus epinephrine; albumin 12.5%; albumin 25%; HPMC; and the pig’s own whole blood. The injection of blood resulted in significantly longer mucosal elevations than any other solution. The authors showed that the cushion created with autologous blood does not interfere with visualization during EMR and lasts up to seven times longer than with NS solution. Shastri et al35 also showed that the mucosal elevation persists significantly longer after injecting autologous blood, compared to NS solution, in a resected porcine stomach and autologous blood generated adequate mucosal elevation for the resection of high-quality specimens. Another study investigated the efficacy of different blood components (serum, plasma, and whole blood) in comparison with NS, HA, glycerol, and hydroxyethyl starch for use as a submucosal fluid cushion.37 The study demonstrated that whole blood generates a mucosal elevation that lasts longer than that by all other agents. A Japanese study successfully performed a novel EMR method assisted by submucosal injection of autologous blood in 28 patients with 35 colorectal polyps.36 According to the study’s findings, the injection of autologous blood does not result in complications such as bleeding or perforation and does not negatively affect pathologic examinations.36
Submucosal injection of autologous blood offers several advantages because of its specific properties: its corpuscular components ensure prolonged submucosal elevation and its procoagulatory constituents promote local hemostasis and prevent postinterventional bleeding. Autologous blood appears to be an ideal submucosal injection solution that provides a long-lasting submucosal cushion, and it is safe, economic, readily available, and easy to inject. Autologous blood may be a promising medium for submucosal injection during EMR and ESD. However, procoagulatory constituents in blood can cause clotting in the syringe if an injection is delayed. In addition, human data are lacking regarding autologous blood as a submucosal injection solution. More
Besides the aforementioned solutions, various submucosal injection solutions have been developed and studied for EMR or ESD. These solutions include carboxymethylcellulose,33,38 photo-crosslinkable chitosan hydrogel,39–42 polyethylene glycol maleate citrate-based injectable drug-eluting elastomeric polymer,43 and sodium alginate.44–46
The adequate selection of a submucosal injection solution is required for successful EMR and ESD. Hydroxypropyl methylcellulose is a very effective submucosal injection solution, but its use is limited by its high cost. Because of the cost-effectiveness, a mixture of HA and glycerol appears to be a good candidate for use as a submucosal injection solution. Autologous blood has recently shown promising preliminary results, but human data are lacking. Further research is needed on the longterm outcomes of submucosal injection solutions to enhance the safety and efficacy of EMR and ESD. In addition, the search should be continued for an ideal injection solution for endoscopic procedures.
Submucosal Injection Solutions for EMR and ESD
Submucosal lift duration | Advantages | Disadvantages | |
---|---|---|---|
Normal saline | + | Cheap, readily available, easy to inject, safe | Rapidly dissipates (i.e., short cushion duration) |
Hypertonic saline | ++ | Cheap, readily available, easy to inject | Local inflammation, tissue damage |
Hyaluronic acid | +++ | Produces the longest lasting cushion, high successful | Expensive, limited availability, very viscous, may stimulate the growth of residual tumor cells |
Glycerol | ++ | Cheap, readily available | Smoke production |
Dextrose | ++ | Cheap, readily available | Local inflammation, tissue damage |
Fibrinogen mixture | +++ | Long-lasting cushion, easy to inject, keeps the visual field clear by providing a microvascular hemostatic effect, reasonable cost (US $0.2/mL) | Limited availability, risk of contamination and transmission of hepatitis or other viruses |
Hydroxypropyl methylcellulose | +++ | Long-lasting cushion, relatively inexpensive | Local inflammation, tissue damage, very viscous |
Autologous blood | +++ | Long-lasting cushion, inexpensive | Limited human data, clotting in syringe if injection is delayed |
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