Submucosal fluid cushion and EMR: who rules the roost?

Abstract

The primary goal behind the use of a submucosal fluid cushion is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and possibly bleeding.When it comes to evaluating sodium hyaluronate (SH) as a submucosal fluid cushion (SFC) in patients who are undergoing an EMR or endoscopic submucosal dissection (ESD), it was only a matter of time before a randomized clinical trial that addresses the issue was performed. In this month's Gastrointestinal Endoscopy, Yamamoto et al1Yamamoto H. Yahagi N. Oyama T. et al.Usefulness and safety of 0.4% sodium hyaluronate solution as a submucosal fluid “cushion” in endoscopic resection for gastric neoplasms: a prospective multicenter trial.Gastrointest Endosc. 2008; 67: 830-839Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar report on 140 patients with 5-mm to 20-mm gastric intramucosal neoplasms randomized to endoscopic resection (predominantly by ESD) by using either 0.4% SH or normal saline solution for submucosal injection. The investigators concluded that the use of 0.4% SH as a submucosal injection solution at an endoscopic resection reduced the need for further injections and simplified the mucosal resection. Is this enough evidence to abandon your normal saline solution supplies and invest in SH?At first glance, the use of the more viscous SH makes intuitive sense. The primary goal behind the use of an SFC is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and, possibly, bleeding.2Farrell J.J. Lauwers G.Y. Brugge W.R. Endoscopic mucosal resection using a cap-fitted endoscope improves tissue resection and pathology interpretation: an animal study.Gastric Cancer. 2006; 9: 3-8Crossref PubMed Scopus (21) Google Scholar Several injections are often necessary during piecemeal resections to isolate the mucosal tissue from injury and prevent delayed, deep-tissue injury. The more durable the SFC, the more likely it will translate into safer procedures. The additional benefit of an SFC includes facilitating the endoscopic resection technique, especially when using a snare.High viscoelasticity, as seen with SH, appears to be an important property of an effective SFC fluid. Viscoelasticity combines the qualities of viscosity (resisting shear flow and strain linearly with time when a stress is applied) and elasticity (straining instantaneously when stretched and quickly returning to the original state once the stress is removed). Whereas, elasticity is usually the result of bond stretching along crystallographic planes in an ordered solid; viscoelasticity is the result of the diffusion of atoms or molecules inside of an amorphous material.3Meyers M.A. Chawla K.A. Viscoelasticity.in: Meyers M.A. Chawla K.A. Mechanical behaviour of materials. Prentice Hall, Upper Saddle River (NJ)1999: 98-103Google Scholar There appears to be a direct correlation between viscoelasticity and the duration of mucosal elevation.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar The electrical characteristics of the SFC fluid may also be another important property. It has been noticed that SFC fluids can considerably influence the electrosurgical performance and that excessive fumes may develop during electrocauterization, which can deteriorate the performance of electrical knives. For example, compared with normal saline solution and SH, fibrinogen has a very high resistance, which may improve the performance of electrosurgery units, probably by heat dissipation.5Park S. Chun H.J. Kim C.Y. et al.Electrical characteristics of various submucosal injection fluids for endoscopic mucosal resection.Dig Dis Sci. 2007 Oct 12; ([Epub ahead of print])Google ScholarOther important properties of the ideal SFC fluid include minimal tissue damage, promotion of ulcer healing, hemostasis, ease of administration, and low cost. Unfortunately, property trade-offs occur. For example, to lengthen the duration of elevation, a higher concentration of saline solution and 20% glucose have been used. By increasing the osmolarity of the solutions (hypertonic saline solution, 20% glucose, 20% mannitol), the duration of elevation is increased but at the cost of increased tissue damage.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar It is known that ulcers can be induced by injecting 50% glucose.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar Glycerol appears to be less tissue damaging.6Fujishiro M. Yahagi N. Kashimura K. et al.Tissue damage of different submucosal injection solutions for EMR.Gastrointest Endosc. 2005; 62: 933-942Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar However, overall, it appears that viscosity is more important than osmolarity for the purpose of maintaining elevation.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google ScholarSH is a type of glycosaminoglycan that is widely found in mammalian connective tissues. It is a thick substance, with high viscoelasticity and a marked ability to retain water that is not antigenic or toxic in human beings. It has been approved for intra-articular injection for osteoarthritis and for ophthalmic procedures in Japan, North America, and Europe. A variety of SH solutions are available. The most commonly used solution in Japanese studies is a 0.5% 800 kDa SH solution made with SH and normal saline solution, because its viscoelasticity enables it to pass through a 23-gauge needle and create an adequate SFC. SH solutions with a high molecular weight (eg, 1900 kDa) have a high viscoelasticity. SH solutions are also best with regard to tissue damage, because they are isotonic to the extracellular fluid.6Fujishiro M. Yahagi N. Kashimura K. et al.Tissue damage of different submucosal injection solutions for EMR.Gastrointest Endosc. 2005; 62: 933-942Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The major disadvantage of SH solutions may be their higher cost ($49.50 to $128 per milliliter in the United States), the lack of regulatory approval, their specific storage requirements, and the need to reconstitute them for use in solution. This compares poorly with other solutions, such as saline/dextrose solution or glycerol, which are available for $0.01 to $0.03 per milliliter. There have also been reports that when SH is used in EMR, it might stimulate the growth of residual tumor.7Matsui Y. Inomata M. Izumi K. et al.Hyaluronic acid stimulates tumor-cell proliferation at wound sites.Gastrointest Endosc. 2004; 60: 539-543Abstract Full Text Full Text PDF PubMed Scopus (68) Google ScholarThe availability of more viscous SFC fluids (including SH, hydroxyl-propyl-methyl-cellulose, fibrinogen, or autologous blood) has generated several comparative ex vivo and in vivo animal studies.8Feitoza A.B. Gostout C.J. Burgart L.J. et al.Hydroxypropyl methylcellulose: a better submucosal fluid cushion for endoscopic mucosal resection.Gastrointest Endosc. 2003; 57: 41-47Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 9Giday S.A. Magno P. Buscaglia J.M. et al.Is blood the ideal submucosal cushioning agent? A comparative study in a porcine model.Endoscopy. 2006; 38: 1230-1234Crossref PubMed Scopus (35) Google Scholar The ex vivo studies that used porcine and canine tissues suggest that, after submucosal injection, higher initial submucosal elevation and slower disappearance of the bleb are seen more commonly with the more viscous agents (SH, fibrinogen, hydroxypropylmethylcellulose) when compared with less viscous materials, such as normal saline solution, hypertonic saline solution, or even dextrose water.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 11Fujishiro M. Yahagi N. Kashimura K. et al.Comparison of various submucosal injection solutions for maintaining mucosal elevation during endoscopic mucosal resection.Endoscopy. 2004; 36: 579-583Crossref PubMed Scopus (243) Google Scholar Nevertheless, a similar histology with a clear separation for the mucosa and submucosa is seen with all types of fluid.The in vivo animal studies that use porcine esophagus and canine stomach and colon, again seem to confirm the higher initial submucosal elevations and the slower disappearance of the SFC with the more viscous materials (including the animal's own blood in one study).9Giday S.A. Magno P. Buscaglia J.M. et al.Is blood the ideal submucosal cushioning agent? A comparative study in a porcine model.Endoscopy. 2006; 38: 1230-1234Crossref PubMed Scopus (35) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Conio M. Rajan E. Sorbi D. et al.Comparative performance in the porcine esophagus of different solutions used for submucosal injection.Gastrointest Endosc. 2002; 56: 513-516Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar For example, in one study, the median and mean disappearance time for SH were more than 19 minutes longer that those for normal saline solution with or without epinephrine.12Conio M. Rajan E. Sorbi D. et al.Comparative performance in the porcine esophagus of different solutions used for submucosal injection.Gastrointest Endosc. 2002; 56: 513-516Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Furthermore, when EMR is performed in vivo, it appears somewhat easier when using the more viscous SFC, likely because of the ability to ensnare the mucosa that results from the steep elevation.10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar However, minor complications and ulcer healing rates appear to be equivalent.10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google ScholarOver time, there have been several case series of EMR and ESD when using combinations of SH, with or without additional sugar and glycerol. All have demonstrated relative safety and efficacy.8Feitoza A.B. Gostout C.J. Burgart L.J. et al.Hydroxypropyl methylcellulose: a better submucosal fluid cushion for endoscopic mucosal resection.Gastrointest Endosc. 2003; 57: 41-47Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 13Yamamoto H. Kawata H. Sunada K. et al.Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood.Endoscopy. 2003; 35: 690-694Crossref PubMed Scopus (381) Google Scholar, 14Yamamoto H. Kawata H. Sunada K. et al.Success rate of curative endoscopic mucosal resection with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate.Gastrointest Endosc. 2002; 56: 507-512Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 15Yamamoto H. Sekine Y. Higashizawa T. et al.Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps.Gastrointest Endosc. 2001; 54: 629-632Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 16Saito Y. Uraoka T. Matsuda T. et al.Endoscopic treatment of large superficial colorectal tumors: a case series of 200 endoscopic submucosal dissections (with video).Gastrointest Endosc. 2007; 66: 966-973Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 17Mukai M. Ito I. Mukoyama S. et al.Endoscopic mucosal resection of superficially spreading colonic neoplasms larger than 5 cm in the right colon after injection of dilute sodium hyaluronate: report of two cases.Endoscopy. 2003; 35: 973-974Crossref PubMed Scopus (20) Google Scholar, 18Yamamoto H. Koiwai H. Yube T. et al.A successful single-step endoscopic resection of a 40 millimeter flat-elevated tumor in the rectum: endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 701-704Abstract Full Text PDF PubMed Scopus (107) Google ScholarThe design of a randomized clinical trial to study SH would be the next logical step. However, several important questions arise in the process of assessing the efficacy of SH as an SFC: what agent should it be compared with and what clinically important outcomes should be measured? Typically, most human studies to date have used normal saline solution as the comparator.19Lee S.H. Park J.H. Park do H. et al.Clinical efficacy of EMR with submucosal injection of a fibrinogen mixture: a prospective randomized trial.Gastrointest Endosc. 2006; 64: 691-696Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 20Varadarajulu S. Tamhane A. Slaughter R.L. Evaluation of dextrose 50% as a medium for injection-assisted polypectomy.Endoscopy. 2006; 38: 907-912Crossref PubMed Scopus (32) Google Scholar Other than its cost and ease of injection, normal saline solution does not appear to have much going for it. So, when the results of the comparison are not that astounding, it makes one wonder whether the more viscous agent is really worth the effort. The more critical issue pertains to deciding upon clinically meaningful primary and secondary outcomes. For example, because piecemeal resections are associated with a high local recurrence rate and incomplete resection, en bloc resection rates may be the single most important outcome.21Miyamoto S. Muto M. Hamamoto Y. et al.A new technique for endoscopic mucosal resection with an insulated-tip electrosurgical knife improves the completeness of resection of intramucosal gastric neoplasms.Gastrointest Endosc. 2002; 55: 576-581Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 22Tanabe S. Koizumi W. Mitomi H. et al.Clinical outcome of endoscopic aspiration mucosectomy for early stage gastric cancer.Gastrointest Endosc. 2002; 56: 708-713Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar In one study that compared fibrinogen with normal saline solution in 72 patients who were undergoing conventional upper-GI EMR of lesions less than 30 mm, there was no significant difference in the primary outcomes, such as en bloc or complete resection rate, complications, and other procedure-related outcomes. One had to look at mean procedure time, mean submucosal injection volume, and the need for additional submucosal injection to maintain the elevation of the lesion to determine any significant benefit for the use of fibrinogen as an SFC.19Lee S.H. Park J.H. Park do H. et al.Clinical efficacy of EMR with submucosal injection of a fibrinogen mixture: a prospective randomized trial.Gastrointest Endosc. 2006; 64: 691-696Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar However, in another study that compared dextrose 50% with normal saline solution for conventional EMR in the stomach and the colon, the only major significant differences in outcomes was in the rate of en bloc resections. The rates of complete resection and complications were equal for both groups, and one had to look at volume of injection and the number of subsequent injections to find other significant differences between the 2 agents.20Varadarajulu S. Tamhane A. Slaughter R.L. Evaluation of dextrose 50% as a medium for injection-assisted polypectomy.Endoscopy. 2006; 38: 907-912Crossref PubMed Scopus (32) Google ScholarIn the current study, ESD rather than EMR was the predominant method of endoscopic resection. Although there was no significant difference between en bloc resection rates, the investigators' calculation of a “usefulness rate,” which incorporates the need for additional injection did show a significant difference between the SH and normal saline solution group. Further analysis reveals that this usefulness rate was only significant for lesions between the sizes of 11 to 15 mm located in the gastric body, although an insignificant trend was seen for lesions between 15 and 20 mm. Again, one had to look at “soft” subjective secondary end points, such as “steepness of mucosal lift” and “ease of resection,” to determine a significant difference between SH and normal saline solution. Interestingly, although there was a significant difference between the volume of fluid injected, there was no difference in the number of intraprocedural complications or the procedure duration. One can conclude that the use of SH makes ESD easier but results in the same en bloc resection, albeit with less need for additional injections during the procedure.At the end of the day, there is still a place for normal saline solution and certain hypertonic solutions, eg, glycerol (which has minimal tissue-damaging effects), in the endoscopist's tool box. The more viscoelastic SFCs, eg, SH, may have a role to play in endoscopic resection, especially ESD of large mucosal processes, although cost and availability appear to be a limitation. The primary goal behind the use of a submucosal fluid cushion is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and possibly bleeding.When it comes to evaluating sodium hyaluronate (SH) as a submucosal fluid cushion (SFC) in patients who are undergoing an EMR or endoscopic submucosal dissection (ESD), it was only a matter of time before a randomized clinical trial that addresses the issue was performed. In this month's Gastrointestinal Endoscopy, Yamamoto et al1Yamamoto H. Yahagi N. Oyama T. et al.Usefulness and safety of 0.4% sodium hyaluronate solution as a submucosal fluid “cushion” in endoscopic resection for gastric neoplasms: a prospective multicenter trial.Gastrointest Endosc. 2008; 67: 830-839Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar report on 140 patients with 5-mm to 20-mm gastric intramucosal neoplasms randomized to endoscopic resection (predominantly by ESD) by using either 0.4% SH or normal saline solution for submucosal injection. The investigators concluded that the use of 0.4% SH as a submucosal injection solution at an endoscopic resection reduced the need for further injections and simplified the mucosal resection. Is this enough evidence to abandon your normal saline solution supplies and invest in SH? The primary goal behind the use of a submucosal fluid cushion is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and possibly bleeding. The primary goal behind the use of a submucosal fluid cushion is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and possibly bleeding. At first glance, the use of the more viscous SH makes intuitive sense. The primary goal behind the use of an SFC is to lift the mucosa to be resected, isolate the lesion, and protect the muscularis propria from thermal and mechanical injury, thereby decreasing the risk of perforation and, possibly, bleeding.2Farrell J.J. Lauwers G.Y. Brugge W.R. Endoscopic mucosal resection using a cap-fitted endoscope improves tissue resection and pathology interpretation: an animal study.Gastric Cancer. 2006; 9: 3-8Crossref PubMed Scopus (21) Google Scholar Several injections are often necessary during piecemeal resections to isolate the mucosal tissue from injury and prevent delayed, deep-tissue injury. The more durable the SFC, the more likely it will translate into safer procedures. The additional benefit of an SFC includes facilitating the endoscopic resection technique, especially when using a snare. High viscoelasticity, as seen with SH, appears to be an important property of an effective SFC fluid. Viscoelasticity combines the qualities of viscosity (resisting shear flow and strain linearly with time when a stress is applied) and elasticity (straining instantaneously when stretched and quickly returning to the original state once the stress is removed). Whereas, elasticity is usually the result of bond stretching along crystallographic planes in an ordered solid; viscoelasticity is the result of the diffusion of atoms or molecules inside of an amorphous material.3Meyers M.A. Chawla K.A. Viscoelasticity.in: Meyers M.A. Chawla K.A. Mechanical behaviour of materials. Prentice Hall, Upper Saddle River (NJ)1999: 98-103Google Scholar There appears to be a direct correlation between viscoelasticity and the duration of mucosal elevation.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar The electrical characteristics of the SFC fluid may also be another important property. It has been noticed that SFC fluids can considerably influence the electrosurgical performance and that excessive fumes may develop during electrocauterization, which can deteriorate the performance of electrical knives. For example, compared with normal saline solution and SH, fibrinogen has a very high resistance, which may improve the performance of electrosurgery units, probably by heat dissipation.5Park S. Chun H.J. Kim C.Y. et al.Electrical characteristics of various submucosal injection fluids for endoscopic mucosal resection.Dig Dis Sci. 2007 Oct 12; ([Epub ahead of print])Google Scholar Other important properties of the ideal SFC fluid include minimal tissue damage, promotion of ulcer healing, hemostasis, ease of administration, and low cost. Unfortunately, property trade-offs occur. For example, to lengthen the duration of elevation, a higher concentration of saline solution and 20% glucose have been used. By increasing the osmolarity of the solutions (hypertonic saline solution, 20% glucose, 20% mannitol), the duration of elevation is increased but at the cost of increased tissue damage.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar It is known that ulcers can be induced by injecting 50% glucose.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar Glycerol appears to be less tissue damaging.6Fujishiro M. Yahagi N. Kashimura K. et al.Tissue damage of different submucosal injection solutions for EMR.Gastrointest Endosc. 2005; 62: 933-942Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar However, overall, it appears that viscosity is more important than osmolarity for the purpose of maintaining elevation.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar SH is a type of glycosaminoglycan that is widely found in mammalian connective tissues. It is a thick substance, with high viscoelasticity and a marked ability to retain water that is not antigenic or toxic in human beings. It has been approved for intra-articular injection for osteoarthritis and for ophthalmic procedures in Japan, North America, and Europe. A variety of SH solutions are available. The most commonly used solution in Japanese studies is a 0.5% 800 kDa SH solution made with SH and normal saline solution, because its viscoelasticity enables it to pass through a 23-gauge needle and create an adequate SFC. SH solutions with a high molecular weight (eg, 1900 kDa) have a high viscoelasticity. SH solutions are also best with regard to tissue damage, because they are isotonic to the extracellular fluid.6Fujishiro M. Yahagi N. Kashimura K. et al.Tissue damage of different submucosal injection solutions for EMR.Gastrointest Endosc. 2005; 62: 933-942Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The major disadvantage of SH solutions may be their higher cost ($49.50 to $128 per milliliter in the United States), the lack of regulatory approval, their specific storage requirements, and the need to reconstitute them for use in solution. This compares poorly with other solutions, such as saline/dextrose solution or glycerol, which are available for $0.01 to $0.03 per milliliter. There have also been reports that when SH is used in EMR, it might stimulate the growth of residual tumor.7Matsui Y. Inomata M. Izumi K. et al.Hyaluronic acid stimulates tumor-cell proliferation at wound sites.Gastrointest Endosc. 2004; 60: 539-543Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The availability of more viscous SFC fluids (including SH, hydroxyl-propyl-methyl-cellulose, fibrinogen, or autologous blood) has generated several comparative ex vivo and in vivo animal studies.8Feitoza A.B. Gostout C.J. Burgart L.J. et al.Hydroxypropyl methylcellulose: a better submucosal fluid cushion for endoscopic mucosal resection.Gastrointest Endosc. 2003; 57: 41-47Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 9Giday S.A. Magno P. Buscaglia J.M. et al.Is blood the ideal submucosal cushioning agent? A comparative study in a porcine model.Endoscopy. 2006; 38: 1230-1234Crossref PubMed Scopus (35) Google Scholar The ex vivo studies that used porcine and canine tissues suggest that, after submucosal injection, higher initial submucosal elevation and slower disappearance of the bleb are seen more commonly with the more viscous agents (SH, fibrinogen, hydroxypropylmethylcellulose) when compared with less viscous materials, such as normal saline solution, hypertonic saline solution, or even dextrose water.4Jin Hyun J. Rae Chun H. Jai Chun H. et al.Comparison of the characteristics of submucosal injection solutions used in endoscopic mucosal resection.Scand J Gastroenterol. 2006; 41: 488-492Crossref PubMed Scopus (50) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 11Fujishiro M. Yahagi N. Kashimura K. et al.Comparison of various submucosal injection solutions for maintaining mucosal elevation during endoscopic mucosal resection.Endoscopy. 2004; 36: 579-583Crossref PubMed Scopus (243) Google Scholar Nevertheless, a similar histology with a clear separation for the mucosa and submucosa is seen with all types of fluid. The in vivo animal studies that use porcine esophagus and canine stomach and colon, again seem to confirm the higher initial submucosal elevations and the slower disappearance of the SFC with the more viscous materials (including the animal's own blood in one study).9Giday S.A. Magno P. Buscaglia J.M. et al.Is blood the ideal submucosal cushioning agent? A comparative study in a porcine model.Endoscopy. 2006; 38: 1230-1234Crossref PubMed Scopus (35) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 12Conio M. Rajan E. Sorbi D. et al.Comparative performance in the porcine esophagus of different solutions used for submucosal injection.Gastrointest Endosc. 2002; 56: 513-516Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar For example, in one study, the median and mean disappearance time for SH were more than 19 minutes longer that those for normal saline solution with or without epinephrine.12Conio M. Rajan E. Sorbi D. et al.Comparative performance in the porcine esophagus of different solutions used for submucosal injection.Gastrointest Endosc. 2002; 56: 513-516Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Furthermore, when EMR is performed in vivo, it appears somewhat easier when using the more viscous SFC, likely because of the ability to ensnare the mucosa that results from the steep elevation.10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar However, minor complications and ulcer healing rates appear to be equivalent.10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Over time, there have been several case series of EMR and ESD when using combinations of SH, with or without additional sugar and glycerol. All have demonstrated relative safety and efficacy.8Feitoza A.B. Gostout C.J. Burgart L.J. et al.Hydroxypropyl methylcellulose: a better submucosal fluid cushion for endoscopic mucosal resection.Gastrointest Endosc. 2003; 57: 41-47Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 10Yamamoto H. Yube T. Isoda N. et al.A novel method of endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 251-256Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 13Yamamoto H. Kawata H. Sunada K. et al.Successful en-bloc resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood.Endoscopy. 2003; 35: 690-694Crossref PubMed Scopus (381) Google Scholar, 14Yamamoto H. Kawata H. Sunada K. et al.Success rate of curative endoscopic mucosal resection with circumferential mucosal incision assisted by submucosal injection of sodium hyaluronate.Gastrointest Endosc. 2002; 56: 507-512Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar, 15Yamamoto H. Sekine Y. Higashizawa T. et al.Successful en bloc resection of a large superficial gastric cancer by using sodium hyaluronate and electrocautery incision forceps.Gastrointest Endosc. 2001; 54: 629-632Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 16Saito Y. Uraoka T. Matsuda T. et al.Endoscopic treatment of large superficial colorectal tumors: a case series of 200 endoscopic submucosal dissections (with video).Gastrointest Endosc. 2007; 66: 966-973Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 17Mukai M. Ito I. Mukoyama S. et al.Endoscopic mucosal resection of superficially spreading colonic neoplasms larger than 5 cm in the right colon after injection of dilute sodium hyaluronate: report of two cases.Endoscopy. 2003; 35: 973-974Crossref PubMed Scopus (20) Google Scholar, 18Yamamoto H. Koiwai H. Yube T. et al.A successful single-step endoscopic resection of a 40 millimeter flat-elevated tumor in the rectum: endoscopic mucosal resection using sodium hyaluronate.Gastrointest Endosc. 1999; 50: 701-704Abstract Full Text PDF PubMed Scopus (107) Google Scholar The design of a randomized clinical trial to study SH would be the next logical step. However, several important questions arise in the process of assessing the efficacy of SH as an SFC: what agent should it be compared with and what clinically important outcomes should be measured? Typically, most human studies to date have used normal saline solution as the comparator.19Lee S.H. Park J.H. Park do H. et al.Clinical efficacy of EMR with submucosal injection of a fibrinogen mixture: a prospective randomized trial.Gastrointest Endosc. 2006; 64: 691-696Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 20Varadarajulu S. Tamhane A. Slaughter R.L. Evaluation of dextrose 50% as a medium for injection-assisted polypectomy.Endoscopy. 2006; 38: 907-912Crossref PubMed Scopus (32) Google Scholar Other than its cost and ease of injection, normal saline solution does not appear to have much going for it. So, when the results of the comparison are not that astounding, it makes one wonder whether the more viscous agent is really worth the effort. The more critical issue pertains to deciding upon clinically meaningful primary and secondary outcomes. For example, because piecemeal resections are associated with a high local recurrence rate and incomplete resection, en bloc resection rates may be the single most important outcome.21Miyamoto S. Muto M. Hamamoto Y. et al.A new technique for endoscopic mucosal resection with an insulated-tip electrosurgical knife improves the completeness of resection of intramucosal gastric neoplasms.Gastrointest Endosc. 2002; 55: 576-581Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 22Tanabe S. Koizumi W. Mitomi H. et al.Clinical outcome of endoscopic aspiration mucosectomy for early stage gastric cancer.Gastrointest Endosc. 2002; 56: 708-713Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar In one study that compared fibrinogen with normal saline solution in 72 patients who were undergoing conventional upper-GI EMR of lesions less than 30 mm, there was no significant difference in the primary outcomes, such as en bloc or complete resection rate, complications, and other procedure-related outcomes. One had to look at mean procedure time, mean submucosal injection volume, and the need for additional submucosal injection to maintain the elevation of the lesion to determine any significant benefit for the use of fibrinogen as an SFC.19Lee S.H. Park J.H. Park do H. et al.Clinical efficacy of EMR with submucosal injection of a fibrinogen mixture: a prospective randomized trial.Gastrointest Endosc. 2006; 64: 691-696Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar However, in another study that compared dextrose 50% with normal saline solution for conventional EMR in the stomach and the colon, the only major significant differences in outcomes was in the rate of en bloc resections. The rates of complete resection and complications were equal for both groups, and one had to look at volume of injection and the number of subsequent injections to find other significant differences between the 2 agents.20Varadarajulu S. Tamhane A. Slaughter R.L. Evaluation of dextrose 50% as a medium for injection-assisted polypectomy.Endoscopy. 2006; 38: 907-912Crossref PubMed Scopus (32) Google Scholar In the current study, ESD rather than EMR was the predominant method of endoscopic resection. Although there was no significant difference between en bloc resection rates, the investigators' calculation of a “usefulness rate,” which incorporates the need for additional injection did show a significant difference between the SH and normal saline solution group. Further analysis reveals that this usefulness rate was only significant for lesions between the sizes of 11 to 15 mm located in the gastric body, although an insignificant trend was seen for lesions between 15 and 20 mm. Again, one had to look at “soft” subjective secondary end points, such as “steepness of mucosal lift” and “ease of resection,” to determine a significant difference between SH and normal saline solution. Interestingly, although there was a significant difference between the volume of fluid injected, there was no difference in the number of intraprocedural complications or the procedure duration. One can conclude that the use of SH makes ESD easier but results in the same en bloc resection, albeit with less need for additional injections during the procedure. At the end of the day, there is still a place for normal saline solution and certain hypertonic solutions, eg, glycerol (which has minimal tissue-damaging effects), in the endoscopist's tool box. The more viscoelastic SFCs, eg, SH, may have a role to play in endoscopic resection, especially ESD of large mucosal processes, although cost and availability appear to be a limitation. DisclosureThe author reports that there are no disclosures relevant to this publication. The author reports that there are no disclosures relevant to this publication.