Scandinavian Journal of Gastroenterology. 2014; Early Online, 1–6
ORIGINAL ARTICLE
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Upper gastrointestinal active bleeding ulcers: review of literature on the results of endoscopic techniques and our experience with Hemospray
ENZO MASCI, MONICA ARENA, ELISABETTA MORANDI, PAOLO VIAGGI & BENEDETTO MANGIAVILLANO Department of Gastrointestinal Endoscopy, University San Paolo Hospital, Milano, Italy
Abstract Introduction and objectives. Acute gastrointestinal (GI) bleeding can lead from mild to immediately life-threatening clinical conditions. Upper GI bleeding (UGIB) is associated with a mortality of 6–10%. Spurting and oozing bleeding are associated with major risk of failure. Hemospray (TC-325), a new hemostatic powder, may be useful in these cases. Aim of this study is to review the efficacy of traditional endoscopic treatment in Forrest 1a-1b ulcers and to investigate the usefulness of Hemospray in these patients. Patients and methods. A MEDLINE search was performed and articles that evaluated hemostatic efficacy and rebleeding rate with traditional endoscopic techniques related to Forrest classification were reviewed. Patients with Forrest 1a–1b ulcers were treated with Hemospray, either as monotherapy or in association with other endoscopic techniques. Primary outcome was immediate hemostasis, secondary outcomes were recurrent bleeding and adverse events related to Hemospray use. Results. Analysis of literature showed that mean initial hemostasis success rate in Forrest 1a–1b ulcers was of 92.8%, and mean rebleeding rate was of 13.3%. We enrolled 13 patients treated with Hemospray. Initial hemostasis was achieved in 100% and we reported three cases of rebleeding. No adverse events occurred. Conclusion. Forrest 1a–1b bleeding ulcer is very difficult to treat. Hemospray appears to be an effective hemostatic therapy for these ulcers. However, additional prospective studies are needed to validate these findings.
Key Words: hemospray, peptic ulcers, upper bleeding.
Introduction Acute gastrointestinal (GI) bleeding can lead from mild to immediately life-threatening clinical conditions. It has an incidence of 100 cases per 100,000 population per year, and remains a common cause of hospitalization and consultation among acute care surgeons [1]. Sung and colleagues determined that peptic ulcer remains the most common and most significant cause of nonvariceal upper GI bleeding (UGIB) but most patients with bleeding from peptic ulcer disease, about 80% died of nonbleeding-related causes [2]. Endoscopy within 24 h of presentation is recommended for management of NVUGIB. Three studies from the USA recently indicated that patients
hospitalized over the weekends for NVUGIB have a higher mortality, probably related to the longer endoscopy waiting time [3,4]. One of the main risk factors for failure of endoscopic hemostasis or rebleeding is strictly related with Forrest classification [5] and spurting and oozing active bleeding (Forrest 1a–1b) are the most difficult to treat. Recently, a new hemostatic powder, Hemospray (Cook Medical, Inc., Winston-Salem, North Carolina, USA), active in acute bleeding, has been introduced. Hemospray is a novel powder licensed for endoscopic treatment, which has been used for many years on the battlefield to control bleeding, particularly from irregularly shaped and high-pressure arterial wounds. The Hemospray material is a proprietary
Correspondence: Enzo Masci, MD, Department of Gastrointestinal Endoscopy, University San Paolo Hospital, Via A. di Rudinì 8, 20142 Milano, Italy. Tel: +0039 02 81844273. Fax: +0039 02 81844467. E-mail: [email protected]
(Received 9 April 2014; revised 30 June 2014; accepted 3 July 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.946080
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inorganic powder. It contains no botanicals or proteins from humans or animals. The material works in two different ways: as a mechanical barrier and by absorption. When in contact with the bleeding site, first the powder forms a barrier over the vessel wall, quickly stopping the bleeding, and second, the absorbent powder increases the local concentration of clotting factors and enhances clot formation. Because the Hemospray powder cannot be taken in by mucosal tissues, absorption and metabolism of the powder do not occur in the body, thereby eliminating the risk of systemic toxicity. The delivery device consists of a syringe containing the Hemospray powder (21 g per syringe), a delivery catheter that is inserted into the working channel of the endoscope, and an introducer handle with a built-in carbon dioxide canister to propel the Hemospray powder out of the catheter [6]. Moreover, Hemospray has been shown to achieve hemostasis in an animal model and in humans with peptic ulcer bleeding [7-9]. Aim of this study is to perform a descriptive review of the literature on the results of traditional endoscopic treatment in Forrest 1a + 1b ulcers bleeding and then to investigate the effectiveness of Hemospray in active UGIB. Materials and methods Analysis of the literature A MEDLINE search was performed by using the following terms: “upper gastrointestinal bleeding”, “acute ulcer bleeding”, “peptic bleeding ulcer”, “endoscopic treatment”, “endoscopic re-treatment”, “recurrent bleeding”, “treatment outcome”, “Forrest classification ulcer bleeding” and “Forrest classification rebleeding.” The search covered the period from 1996 to January 2013. Manual searches of reference lists from potentially relevant articles were performed to identify any additional studies that may have been missed using the computer-assisted strategy. Potentially relevant studies were retrieved, and selection criteria were applied. The selection criteria were: (a) studies in humans, (b) studies published in the English language, (c) articles that evaluated endoscopic hemostatic efficacy in actively bleeding ulcer (both overall and randomized trial); (d) articles that evaluated the endoscopic outcome related to Forrest classification. Studies without a correlation between Forrest classification and endoscopic treatment success or failure were excluded. We compared and reviewed separately: 1) studies that analyzed initial hemostatic outcome according to Forrest classification and 2) studies evaluating the recurrent bleeding according to Forrest classification.
Forrest classification [10] is defined as follows: Forrest Ia = spurting bleeding, Ib = oozing bleeding, IIa = nonbleeding visible vessel, IIb = adherent clot, IIc = hematin on ulcer base and III = clean ulcer base. Study protocol Patients were eligible if they were above the age of 18 years and had endoscopic confirmation of a bleeding peptic ulcer with a Forrest score of Ia (spurting hemorrhage) or Ib (oozing hemorrhage) within 24 h of hospital admission. Patients presenting to our unit with actively bleeding ulcers (Forrest 1a-1b) were treated with Hemospray. Data on sex, age, medication use, procedural details and outcome were collected. Endoscopic hemostatic interventions (used endoscopes: Pentax EG 2990I–1T; Pentax Hamburg, Germany) were performed exclusively by expert endoscopists who were experienced in therapeutic endoscopy for UGIB and were specially trained in Hemospray application. These patients underwent upper endoscopy performing hemostasis of UGIB with Hemospray. If Hemospray did not cause the immediate arrest of bleeding would be used the endoscopic haemostatic devices currently in use. The primary outcome measure was immediate hemostasis (defined as the cessation of active bleeding as observed endoscopically for 5 min after Hemospray application both in monotherapy and combined therapy). Secondary outcome measures were (1) recurrent early bleeding (defined as clinical evidence of digestive hemorrhage or a hemoglobin decrease of more than 2 g/dl within 24–72 h after Hemospray application) and delayed rebleeding (after 72 h), (2) adverse events possibly related to Hemospray application. A standard scheduled second-look endoscopy was carried out after 48– 72 h from the first endoscopy. Treatment failure was defined either as the inability to achieve immediate hemostasis. All endoscopists performing procedures had a previous training in Hemospray use. The training consisted of a theoretical part and hands-on training on a model. Hemospray (maximum 20 g) was applied onto the active bleeding site through a 10-Fr catheter (Cook Medical) in short bursts of a CO2-propelled canister until hemostasis was confirmed. Hemospray was used either as monotherapy or in association with other hemostatic endoscopic modalities. Patients were resuscitated as needed to achieve hemodynamic stability in preparation for endoscopy. The study was approved by the institutional review board, and all patients provided written, informed consent for study participation.
Hemospray and active bleeding ulcers
Eight studies evaluated the rebleeding rate in the F Ia and F Ib subgroups [11,15,22-27], while the other five considered the rebleeding percentage in all F I ulcer bleeding (F Ia + F Ib) [14,16,17,20,21]. We reviewed a total of 1917 patients with a number of 1167 of F Ia + F Ib with a mean rebleeding rate of 13.3% (range of 0–61.1%). Results are summarized in Table II.
Results Analysis of literature
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Initial hemostatis. Eleven articles were found in literature about the endoscopic hemostasis success of upper ulcer bleeding according to Forrest classification. All these were randomized trial that compared two or more endoscopic therapeutic approach. Most of them assessed the endoscopic efficacy of different hemostatic therapy in Forrest I–II and only two of these considered exclusively Forrest I ulcer bleeding [11,12]. Four studies evaluated the hemostatic efficacy of Forrest I ulcer divided in two subgroups of F Ia and F Ib, respectively [11,13-15], while all the others assessed the whole F I (a + b) success rate. Results are summarized in Table I [12,16-21]. A total of 1803 patients were enrolled in all the studies with 1176 cases of F Ia + F Ib. The initial hemostasis success rate in Forrest I (Ia + Ib) ranged from 60% to 100%, with a mean value of 92.8%.
Hemospray – results Thirteen patients were enrolled in our study and treated according to the protocol requirements. Patient demographics, clinical presentations, ulcer characteristics and procedural results are summarized in Table III. We observed that, in actively high-risk ulcer bleeding (F Ia and F Ib), the new hemostatic powder Hemospray allows to obtain an initial hemostasis of 100%, a permanent hemostasis of 84.6% with a rebleeding rate of 15.4%. The initial hemostasis was achieved in 13 patients, 8 cases were obtained with Hemospray in monotherapy and 6 cases with combined endoscopic therapy. Among these, Hemospray has been used to achieve hemostasis after
Recurrent bleeding. We found 13 articles in literature assessing the rebleeding rate in ulcers related to Forrest classification.
Table I. Successful hemostatic rates, number (%) in Forrest I classification. Author (reference)
Chau et al. [15] Lee et al. [17] Chung et al. [13]
Bianco et al. [16] Chung et al. [12] Soon et al. [14] Chung et al. [13] Church et al. [21] Cipolletta et al. [19] Laine et al. [18] Liou et al. [20]
Total
Total pt
97 88 63 63 41 41 42 56 58 134 136 74 74 81 79 127 120 57 56 48 52 72 72 72 1803
F Ia
F Ib
F Ia + FI b
8 4
47 43
7 2 6
13 12 15
27 31 7 6 18 17
107 105 49 37 63 62
5 6
15 13
15 14 17 190
57 58 55 751
55 47 31 32 20 14 21 19 19 134 136 56 43 81 79 49 45 20 19 17 23 72 72 72 1176
Hemostasis F Ia N (%)
Hemostasis F Ib N (%)
7/8 (87.5%) 4/4 (100%)
44/47 (93.6%) 41/43 (93.2%)
5/7 (71.4%) 1/2 (50%) 4/6 (66.7%)
13/13 (100%) 10/12 (83.3%) 15/15 (100%)
25/27 31/31 5/7 0/6
(92.6%) (100%) (71%) (0%)
106/107(99%) 104/105 (99%) 49/49 (100%) 33/37 (89%)
82/98 (83.6%)
415/428 (96.9%)
Hemostasis F Ia + F Ib N (%)
Endoscopic technique divided per group
51/55 45/47 26/31 29/32 18/20 11/14 19/21 13/19 19/19 131/134 135/136 54/56 33/43 79/81 75/79 46/49 42/45 12/20 13/19 13/17 22/23 71/72 64/72 71/72 1092/1176
ad ad f a b a ab c ac a ac d ad a ad ed ed b d e d a e e
(92.7%) (95.7%) (83.9%) (90.6%) (90%) (78.6%) (90.5%) (68.4%) (100%) (97.7%) (99.2%) (96.4%) (76.7%) (97.5%) (94.9%) (94%) (93%) (60%) (68%) (76%) (96%) (98.6%) (88.9%) (98.6%) (92.8%)
a = Epinephrine injection; b = Hemoclip; c = Gold probe; d = Other thermal therapy (argon, heater probe, bipolar; e = Other injection therapy (normal saline solution, human thrombin, large volume epinephrine); f = Fibrin glue or cyanoacrylate; combined therapy: association of symbols of the different therapy.
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Table II. Rebleeding rate, number (%) in Forrest I classification. Author (reference)
Chau et al. [15] Lee et al. [17] Bianco et al. [16] Chung et al. [12]
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Soon et al. [14] Church et al. [21] Liou et al. [20]
Park et al. [22] Buffoli et al. [23] Lin et al. [24] Lin et al. [26] Pescatore et al. [25] Lin et al. [27] Total
Total pt
97 88 63 63 56 58 134 136 74 74 127 120 72 72 72 45 45 54 45 40 40 78 78 70 65 26 25 1917
F Ia
F Ib
F Ia + FI b
8 4
47 43
27 31
107 105
15 14 17 9 9 3 5 9 8 9 11 7 8 7 9 210
57 58 55 15 13 16 11 11 11 23 27 25 22 8 9 663
55 47 31 32 19 19 134 136 56 43 49 45 72 72 72 24 22 19 16 20 19 32 38 32 30 15 18 1167
Rebleeding F Ia N (%)
3/8 (37.5%) 1/4 (21.2%)
6/27 (22%) 2/31 (6.5%)
1/9 3/8 0/3 0/5 0/9 2/8 6/9 3/11 4/7 2/8 2/7 7/9 42/163
(11%) (37.5%) (0%) (0%) (0%) (25%) (66.6%) (27.3%) (57%) (25%) (28.6%) (77.7)% (25.7%)
Rebleeding F Ib N (%)
10/47 (25%) 9/43 (20.9%)
6/107 (5.6%) 3/105 (2.9%)
1/14 3/13 5/16 0/11 0/11 0/11 7/23 4/27 6/25 3/22 1/8 4/9 62/492
(7.1%) (23%) (31.25%) (0%) (0%) (0%) (30.4%) (14.8%) (24%) (14%) (12.5%) (44.4%) (12.6%)
Rebleeding F Ia + F Ib N (%)
Endoscopic technique divided per group
13/55 10/47 11/26 4/29 3/13 1/19 12/134 5/136 0/56 4/43 8/46 5/42 3/69 4/64 4/71 2/23 6/21 5/19 0/16 0/20 2/19 13/32 7/38 10/32 5/30 3/15 11/18 151/1133
ad ad e a c ac a ac d ad ed ed a e e ab a a ab b d a e a af af a
(23.6%) (21.3%) (42.3%) (13.8%) (23%) (5.2%) (8.95%) (3.6%) (0%) (5.4)% (17%) (12%) (4.3%) (6.3%) (5.6%) (8.7%) (28.6%) (26.3%) (0%) (0%) (10.5%) (40.6%) (18.4%) (31.25%) (16.6%) (20%) (61.1%) (13.3%)
a = Epinephrine injection; b = Hemoclip; c = Gold probe; d = Other thermal therapy (argon, heater probe, bipolar); e = Other injection therapy (large volume epinephrine, normal saline solution); f, Fibrin glue or cyanoacrylate; combined therapy: association of symbols of the different therapy.
standard endoscopic treatment in three large duodenal ulcers (2 F1a and 1 F1b), and in the other three cases we used other endoscopic treatment after initial Table III. Clinical and endoscopic details of our patients. Mean age Sex (M/F) Melena Hematemesis Forrest Ia Forrest Ib Ulcer location Duodenal Gastric Anastomosis Recent NSAIDs intake Oral anticoagulant therapy Hemospray monotherapy Combined therapy* Immediate hemostasis Permanent hemostasis Rebleeding
70.3 years (range 42–88) 9/4 8 5 4 9 9 3 1 6 3 7 6 13/13 11/13 2/13
(69.2 vs. 30.8%) (57.1%) (42.8%) (35.7%) (64.3%) (69.2%) (23.1%) (7.7%) (46.2%) (23.1%) (53.8%) (46.2%) (100%) (84.6%) (15.4%)
*Hemospray plus other endoscopic modalities (epinephrine injection, clips and both epinephrine and clips).
failure of Hemospray (two very small fundic gastric F1a ulcers and in one anastomotic F1a ulcer). Each patient underwent a second upper GI endoscopy within 72 h of first. Eleven cases confirmed a permanent hemostasis, also in patients on oral anticoagulant therapy. We observed two cases of rebleeding, one with F Ib and one with F Ia ulcer, one case was early and one delayed recurrent bleeding. Among the patients with rebleeding, one was initially treated only with Hemospray and one with combined therapy. Both rebleeding cases were retreated, one or twice, with other endoscopic conventional hemostatic technique (epinephrine and clips), but none of them was successful and they underwent surgery. No adverse events occurred. Discussion Although endoscopic therapy significantly improves outcomes in patients with UGIB in which initial hemostasis is achieved in >90%, rebleeding is still reported in 10–20% after successful initial hemostasis
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Hemospray and active bleeding ulcers [28-32] and the mortality rate is still ~5–10% in patients with UGIB [11,15,29]. Therefore, the most important goal of endoscopic therapy is to initially achieve permanent hemostasis. As outlined in a recent guideline of Laine [33], endoscopic stigmata of active bleeding is associated with a high risk of further bleeding, surgery for bleeding and mortality (respectively 55%, 35% and 11%), than the other low-risk stigmata. From the analysis of the literature, actively bleeding ulcer (F Ia + F Ib) reach an average rate of endoscopic hemostasis of 92.8% and have a rebleeding mean rate of 13.3%, but if we considered the range of success and recurrent bleeding in each study the value are extremely variable. Moreover, if we analyzed only F Ia ulcers, the initial hemostasis rate is 83.6% and the rebleeding rate is 25.7%. Studies in the literature are very heterogeneous with regard to the type of haemostatic technique used and for the sample size of patients enrolled, and consequently is difficult to draw firm conclusions. In our study we found that, in actively high-risk ulcer bleeding (F Ia and F Ib), the new hemostatic powder Hemospray allows to obtain an initial hemostasis of 100%, a permanent hemostasis of 84.6% with a rebleeding rate of 15.4%. Among the two cases with rebleeding, one was due to ulcer on a Billroth II anastomosis in a recent excessive intake of NSAIDs. The biggest study actually published in literature on endoscopic hemostasis with Hemospray is from Smith LA et al. on 63 patients with NVUGIB. There were 30 patients with bleeding ulcers and 33 with other NVUGIB pathology. Fifty-five (87%) patients were treated with Hemospray as monotherapy; 47 (85%) of them achieved primary hemostasis and rebleeding rate at 7 days was 15%. Primary hemostasis rate for Hemospray in patients with ulcer bleeds was 76%. Eight patients, who otherwise may have required either surgery or interventional radiology, were treated with Hemospray as second-line therapy after failure of other endoscopic treatments, all of whom achieved hemostasis following the adjunct of Hemospray [34]. Hemostasis failure and rebleeding rate are major in Forrest high-risk stigma, and for these reasons it is still necessary to find new endoscopic methods to treat these kinds of active ulcer bleeding and reduce related mortality. Nowadays, only few studies are published in literature on the efficacy of Hemospray in NVUGIB. Sung et al. [9] conducted a pilot study to evaluate the hemostatic efficacy of Hemospray in spurting and oozing ulcer bleeding. They enrolled 20 patients with active ulcer bleeding (19 F Ib and 1 F Ia) who were treated with one or two application of Hemospray. In case of failure of hemostasis, a traditional endoscopic
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approach was then performed. They obtained an initial successful hemostasis of 95% and a permanent hemostasis in 89.5% while recurrent bleeding was observed in two patients (10.5%). Results of this study are slightly better than ours, though we have enrolled a greater number of F Ia ulcer bleeding. Holster et al. [35] performed a study to assess Hemospray treatment outcome in patients on antithrombotic therapy (ATT), compared with patients not receiving such treatment at time of GI bleeding. UIGB in patients on ATT can be hard to treat with current endoscopic modalities and therefore novel approach should be evaluated. They enrolled 16 patients with UGIB of which 9 were due to peptic ulcer bleeding (4 F Ia and 5 F Ib). Eight patients were on ATT and, in this subgroup, immediate hemostasis after Hemospray was 63% while in the nonantithrombotic group was 100%. Global successful hemostasis was obtained in 81% of patients. Rebleeding rate was 38% in antithrombotic group and 25% in the whole number of patients was 31%. Sometimes successful hemostasis can be technically difficult to achieve because of large dimension or particular position of the ulcer. In these circumstances, Hemospray could be considered the ideal hemostatic endoscopic agent because it does not require a direct contact with the bleeding site. Hemospray can be used as monotherapy or in combination with other endoscopic treatment. To date, there are no definite indications for its use as monotherapy or in combination, but according to our experience, we can say that in small size F1a bleeding lesions, Hemospray in monotherapy is less effective. In conclusion, Hemospray appears to be an effective hemostatic therapy for bleeding ulcers F1a and 1b. Additional prospective studies are needed to further validate these findings. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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ORIGINAL ARTICLE
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Upper gastrointestinal active bleeding ulcers: review of literature on the results of endoscopic techniques and our experience with Hemospray
ENZO MASCI, MONICA ARENA, ELISABETTA MORANDI, PAOLO VIAGGI & BENEDETTO MANGIAVILLANO Department of Gastrointestinal Endoscopy, University San Paolo Hospital, Milano, Italy
Abstract Introduction and objectives. Acute gastrointestinal (GI) bleeding can lead from mild to immediately life-threatening clinical conditions. Upper GI bleeding (UGIB) is associated with a mortality of 6–10%. Spurting and oozing bleeding are associated with major risk of failure. Hemospray (TC-325), a new hemostatic powder, may be useful in these cases. Aim of this study is to review the efficacy of traditional endoscopic treatment in Forrest 1a-1b ulcers and to investigate the usefulness of Hemospray in these patients. Patients and methods. A MEDLINE search was performed and articles that evaluated hemostatic efficacy and rebleeding rate with traditional endoscopic techniques related to Forrest classification were reviewed. Patients with Forrest 1a–1b ulcers were treated with Hemospray, either as monotherapy or in association with other endoscopic techniques. Primary outcome was immediate hemostasis, secondary outcomes were recurrent bleeding and adverse events related to Hemospray use. Results. Analysis of literature showed that mean initial hemostasis success rate in Forrest 1a–1b ulcers was of 92.8%, and mean rebleeding rate was of 13.3%. We enrolled 13 patients treated with Hemospray. Initial hemostasis was achieved in 100% and we reported three cases of rebleeding. No adverse events occurred. Conclusion. Forrest 1a–1b bleeding ulcer is very difficult to treat. Hemospray appears to be an effective hemostatic therapy for these ulcers. However, additional prospective studies are needed to validate these findings.
Key Words: hemospray, peptic ulcers, upper bleeding.
Introduction Acute gastrointestinal (GI) bleeding can lead from mild to immediately life-threatening clinical conditions. It has an incidence of 100 cases per 100,000 population per year, and remains a common cause of hospitalization and consultation among acute care surgeons [1]. Sung and colleagues determined that peptic ulcer remains the most common and most significant cause of nonvariceal upper GI bleeding (UGIB) but most patients with bleeding from peptic ulcer disease, about 80% died of nonbleeding-related causes [2]. Endoscopy within 24 h of presentation is recommended for management of NVUGIB. Three studies from the USA recently indicated that patients
hospitalized over the weekends for NVUGIB have a higher mortality, probably related to the longer endoscopy waiting time [3,4]. One of the main risk factors for failure of endoscopic hemostasis or rebleeding is strictly related with Forrest classification [5] and spurting and oozing active bleeding (Forrest 1a–1b) are the most difficult to treat. Recently, a new hemostatic powder, Hemospray (Cook Medical, Inc., Winston-Salem, North Carolina, USA), active in acute bleeding, has been introduced. Hemospray is a novel powder licensed for endoscopic treatment, which has been used for many years on the battlefield to control bleeding, particularly from irregularly shaped and high-pressure arterial wounds. The Hemospray material is a proprietary
Correspondence: Enzo Masci, MD, Department of Gastrointestinal Endoscopy, University San Paolo Hospital, Via A. di Rudinì 8, 20142 Milano, Italy. Tel: +0039 02 81844273. Fax: +0039 02 81844467. E-mail: [email protected]
(Received 9 April 2014; revised 30 June 2014; accepted 3 July 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.946080
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inorganic powder. It contains no botanicals or proteins from humans or animals. The material works in two different ways: as a mechanical barrier and by absorption. When in contact with the bleeding site, first the powder forms a barrier over the vessel wall, quickly stopping the bleeding, and second, the absorbent powder increases the local concentration of clotting factors and enhances clot formation. Because the Hemospray powder cannot be taken in by mucosal tissues, absorption and metabolism of the powder do not occur in the body, thereby eliminating the risk of systemic toxicity. The delivery device consists of a syringe containing the Hemospray powder (21 g per syringe), a delivery catheter that is inserted into the working channel of the endoscope, and an introducer handle with a built-in carbon dioxide canister to propel the Hemospray powder out of the catheter [6]. Moreover, Hemospray has been shown to achieve hemostasis in an animal model and in humans with peptic ulcer bleeding [7-9]. Aim of this study is to perform a descriptive review of the literature on the results of traditional endoscopic treatment in Forrest 1a + 1b ulcers bleeding and then to investigate the effectiveness of Hemospray in active UGIB. Materials and methods Analysis of the literature A MEDLINE search was performed by using the following terms: “upper gastrointestinal bleeding”, “acute ulcer bleeding”, “peptic bleeding ulcer”, “endoscopic treatment”, “endoscopic re-treatment”, “recurrent bleeding”, “treatment outcome”, “Forrest classification ulcer bleeding” and “Forrest classification rebleeding.” The search covered the period from 1996 to January 2013. Manual searches of reference lists from potentially relevant articles were performed to identify any additional studies that may have been missed using the computer-assisted strategy. Potentially relevant studies were retrieved, and selection criteria were applied. The selection criteria were: (a) studies in humans, (b) studies published in the English language, (c) articles that evaluated endoscopic hemostatic efficacy in actively bleeding ulcer (both overall and randomized trial); (d) articles that evaluated the endoscopic outcome related to Forrest classification. Studies without a correlation between Forrest classification and endoscopic treatment success or failure were excluded. We compared and reviewed separately: 1) studies that analyzed initial hemostatic outcome according to Forrest classification and 2) studies evaluating the recurrent bleeding according to Forrest classification.
Forrest classification [10] is defined as follows: Forrest Ia = spurting bleeding, Ib = oozing bleeding, IIa = nonbleeding visible vessel, IIb = adherent clot, IIc = hematin on ulcer base and III = clean ulcer base. Study protocol Patients were eligible if they were above the age of 18 years and had endoscopic confirmation of a bleeding peptic ulcer with a Forrest score of Ia (spurting hemorrhage) or Ib (oozing hemorrhage) within 24 h of hospital admission. Patients presenting to our unit with actively bleeding ulcers (Forrest 1a-1b) were treated with Hemospray. Data on sex, age, medication use, procedural details and outcome were collected. Endoscopic hemostatic interventions (used endoscopes: Pentax EG 2990I–1T; Pentax Hamburg, Germany) were performed exclusively by expert endoscopists who were experienced in therapeutic endoscopy for UGIB and were specially trained in Hemospray application. These patients underwent upper endoscopy performing hemostasis of UGIB with Hemospray. If Hemospray did not cause the immediate arrest of bleeding would be used the endoscopic haemostatic devices currently in use. The primary outcome measure was immediate hemostasis (defined as the cessation of active bleeding as observed endoscopically for 5 min after Hemospray application both in monotherapy and combined therapy). Secondary outcome measures were (1) recurrent early bleeding (defined as clinical evidence of digestive hemorrhage or a hemoglobin decrease of more than 2 g/dl within 24–72 h after Hemospray application) and delayed rebleeding (after 72 h), (2) adverse events possibly related to Hemospray application. A standard scheduled second-look endoscopy was carried out after 48– 72 h from the first endoscopy. Treatment failure was defined either as the inability to achieve immediate hemostasis. All endoscopists performing procedures had a previous training in Hemospray use. The training consisted of a theoretical part and hands-on training on a model. Hemospray (maximum 20 g) was applied onto the active bleeding site through a 10-Fr catheter (Cook Medical) in short bursts of a CO2-propelled canister until hemostasis was confirmed. Hemospray was used either as monotherapy or in association with other hemostatic endoscopic modalities. Patients were resuscitated as needed to achieve hemodynamic stability in preparation for endoscopy. The study was approved by the institutional review board, and all patients provided written, informed consent for study participation.
Hemospray and active bleeding ulcers
Eight studies evaluated the rebleeding rate in the F Ia and F Ib subgroups [11,15,22-27], while the other five considered the rebleeding percentage in all F I ulcer bleeding (F Ia + F Ib) [14,16,17,20,21]. We reviewed a total of 1917 patients with a number of 1167 of F Ia + F Ib with a mean rebleeding rate of 13.3% (range of 0–61.1%). Results are summarized in Table II.
Results Analysis of literature
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Initial hemostatis. Eleven articles were found in literature about the endoscopic hemostasis success of upper ulcer bleeding according to Forrest classification. All these were randomized trial that compared two or more endoscopic therapeutic approach. Most of them assessed the endoscopic efficacy of different hemostatic therapy in Forrest I–II and only two of these considered exclusively Forrest I ulcer bleeding [11,12]. Four studies evaluated the hemostatic efficacy of Forrest I ulcer divided in two subgroups of F Ia and F Ib, respectively [11,13-15], while all the others assessed the whole F I (a + b) success rate. Results are summarized in Table I [12,16-21]. A total of 1803 patients were enrolled in all the studies with 1176 cases of F Ia + F Ib. The initial hemostasis success rate in Forrest I (Ia + Ib) ranged from 60% to 100%, with a mean value of 92.8%.
Hemospray – results Thirteen patients were enrolled in our study and treated according to the protocol requirements. Patient demographics, clinical presentations, ulcer characteristics and procedural results are summarized in Table III. We observed that, in actively high-risk ulcer bleeding (F Ia and F Ib), the new hemostatic powder Hemospray allows to obtain an initial hemostasis of 100%, a permanent hemostasis of 84.6% with a rebleeding rate of 15.4%. The initial hemostasis was achieved in 13 patients, 8 cases were obtained with Hemospray in monotherapy and 6 cases with combined endoscopic therapy. Among these, Hemospray has been used to achieve hemostasis after
Recurrent bleeding. We found 13 articles in literature assessing the rebleeding rate in ulcers related to Forrest classification.
Table I. Successful hemostatic rates, number (%) in Forrest I classification. Author (reference)
Chau et al. [15] Lee et al. [17] Chung et al. [13]
Bianco et al. [16] Chung et al. [12] Soon et al. [14] Chung et al. [13] Church et al. [21] Cipolletta et al. [19] Laine et al. [18] Liou et al. [20]
Total
Total pt
97 88 63 63 41 41 42 56 58 134 136 74 74 81 79 127 120 57 56 48 52 72 72 72 1803
F Ia
F Ib
F Ia + FI b
8 4
47 43
7 2 6
13 12 15
27 31 7 6 18 17
107 105 49 37 63 62
5 6
15 13
15 14 17 190
57 58 55 751
55 47 31 32 20 14 21 19 19 134 136 56 43 81 79 49 45 20 19 17 23 72 72 72 1176
Hemostasis F Ia N (%)
Hemostasis F Ib N (%)
7/8 (87.5%) 4/4 (100%)
44/47 (93.6%) 41/43 (93.2%)
5/7 (71.4%) 1/2 (50%) 4/6 (66.7%)
13/13 (100%) 10/12 (83.3%) 15/15 (100%)
25/27 31/31 5/7 0/6
(92.6%) (100%) (71%) (0%)
106/107(99%) 104/105 (99%) 49/49 (100%) 33/37 (89%)
82/98 (83.6%)
415/428 (96.9%)
Hemostasis F Ia + F Ib N (%)
Endoscopic technique divided per group
51/55 45/47 26/31 29/32 18/20 11/14 19/21 13/19 19/19 131/134 135/136 54/56 33/43 79/81 75/79 46/49 42/45 12/20 13/19 13/17 22/23 71/72 64/72 71/72 1092/1176
ad ad f a b a ab c ac a ac d ad a ad ed ed b d e d a e e
(92.7%) (95.7%) (83.9%) (90.6%) (90%) (78.6%) (90.5%) (68.4%) (100%) (97.7%) (99.2%) (96.4%) (76.7%) (97.5%) (94.9%) (94%) (93%) (60%) (68%) (76%) (96%) (98.6%) (88.9%) (98.6%) (92.8%)
a = Epinephrine injection; b = Hemoclip; c = Gold probe; d = Other thermal therapy (argon, heater probe, bipolar; e = Other injection therapy (normal saline solution, human thrombin, large volume epinephrine); f = Fibrin glue or cyanoacrylate; combined therapy: association of symbols of the different therapy.
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Table II. Rebleeding rate, number (%) in Forrest I classification. Author (reference)
Chau et al. [15] Lee et al. [17] Bianco et al. [16] Chung et al. [12]
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Soon et al. [14] Church et al. [21] Liou et al. [20]
Park et al. [22] Buffoli et al. [23] Lin et al. [24] Lin et al. [26] Pescatore et al. [25] Lin et al. [27] Total
Total pt
97 88 63 63 56 58 134 136 74 74 127 120 72 72 72 45 45 54 45 40 40 78 78 70 65 26 25 1917
F Ia
F Ib
F Ia + FI b
8 4
47 43
27 31
107 105
15 14 17 9 9 3 5 9 8 9 11 7 8 7 9 210
57 58 55 15 13 16 11 11 11 23 27 25 22 8 9 663
55 47 31 32 19 19 134 136 56 43 49 45 72 72 72 24 22 19 16 20 19 32 38 32 30 15 18 1167
Rebleeding F Ia N (%)
3/8 (37.5%) 1/4 (21.2%)
6/27 (22%) 2/31 (6.5%)
1/9 3/8 0/3 0/5 0/9 2/8 6/9 3/11 4/7 2/8 2/7 7/9 42/163
(11%) (37.5%) (0%) (0%) (0%) (25%) (66.6%) (27.3%) (57%) (25%) (28.6%) (77.7)% (25.7%)
Rebleeding F Ib N (%)
10/47 (25%) 9/43 (20.9%)
6/107 (5.6%) 3/105 (2.9%)
1/14 3/13 5/16 0/11 0/11 0/11 7/23 4/27 6/25 3/22 1/8 4/9 62/492
(7.1%) (23%) (31.25%) (0%) (0%) (0%) (30.4%) (14.8%) (24%) (14%) (12.5%) (44.4%) (12.6%)
Rebleeding F Ia + F Ib N (%)
Endoscopic technique divided per group
13/55 10/47 11/26 4/29 3/13 1/19 12/134 5/136 0/56 4/43 8/46 5/42 3/69 4/64 4/71 2/23 6/21 5/19 0/16 0/20 2/19 13/32 7/38 10/32 5/30 3/15 11/18 151/1133
ad ad e a c ac a ac d ad ed ed a e e ab a a ab b d a e a af af a
(23.6%) (21.3%) (42.3%) (13.8%) (23%) (5.2%) (8.95%) (3.6%) (0%) (5.4)% (17%) (12%) (4.3%) (6.3%) (5.6%) (8.7%) (28.6%) (26.3%) (0%) (0%) (10.5%) (40.6%) (18.4%) (31.25%) (16.6%) (20%) (61.1%) (13.3%)
a = Epinephrine injection; b = Hemoclip; c = Gold probe; d = Other thermal therapy (argon, heater probe, bipolar); e = Other injection therapy (large volume epinephrine, normal saline solution); f, Fibrin glue or cyanoacrylate; combined therapy: association of symbols of the different therapy.
standard endoscopic treatment in three large duodenal ulcers (2 F1a and 1 F1b), and in the other three cases we used other endoscopic treatment after initial Table III. Clinical and endoscopic details of our patients. Mean age Sex (M/F) Melena Hematemesis Forrest Ia Forrest Ib Ulcer location Duodenal Gastric Anastomosis Recent NSAIDs intake Oral anticoagulant therapy Hemospray monotherapy Combined therapy* Immediate hemostasis Permanent hemostasis Rebleeding
70.3 years (range 42–88) 9/4 8 5 4 9 9 3 1 6 3 7 6 13/13 11/13 2/13
(69.2 vs. 30.8%) (57.1%) (42.8%) (35.7%) (64.3%) (69.2%) (23.1%) (7.7%) (46.2%) (23.1%) (53.8%) (46.2%) (100%) (84.6%) (15.4%)
*Hemospray plus other endoscopic modalities (epinephrine injection, clips and both epinephrine and clips).
failure of Hemospray (two very small fundic gastric F1a ulcers and in one anastomotic F1a ulcer). Each patient underwent a second upper GI endoscopy within 72 h of first. Eleven cases confirmed a permanent hemostasis, also in patients on oral anticoagulant therapy. We observed two cases of rebleeding, one with F Ib and one with F Ia ulcer, one case was early and one delayed recurrent bleeding. Among the patients with rebleeding, one was initially treated only with Hemospray and one with combined therapy. Both rebleeding cases were retreated, one or twice, with other endoscopic conventional hemostatic technique (epinephrine and clips), but none of them was successful and they underwent surgery. No adverse events occurred. Discussion Although endoscopic therapy significantly improves outcomes in patients with UGIB in which initial hemostasis is achieved in >90%, rebleeding is still reported in 10–20% after successful initial hemostasis
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Hemospray and active bleeding ulcers [28-32] and the mortality rate is still ~5–10% in patients with UGIB [11,15,29]. Therefore, the most important goal of endoscopic therapy is to initially achieve permanent hemostasis. As outlined in a recent guideline of Laine [33], endoscopic stigmata of active bleeding is associated with a high risk of further bleeding, surgery for bleeding and mortality (respectively 55%, 35% and 11%), than the other low-risk stigmata. From the analysis of the literature, actively bleeding ulcer (F Ia + F Ib) reach an average rate of endoscopic hemostasis of 92.8% and have a rebleeding mean rate of 13.3%, but if we considered the range of success and recurrent bleeding in each study the value are extremely variable. Moreover, if we analyzed only F Ia ulcers, the initial hemostasis rate is 83.6% and the rebleeding rate is 25.7%. Studies in the literature are very heterogeneous with regard to the type of haemostatic technique used and for the sample size of patients enrolled, and consequently is difficult to draw firm conclusions. In our study we found that, in actively high-risk ulcer bleeding (F Ia and F Ib), the new hemostatic powder Hemospray allows to obtain an initial hemostasis of 100%, a permanent hemostasis of 84.6% with a rebleeding rate of 15.4%. Among the two cases with rebleeding, one was due to ulcer on a Billroth II anastomosis in a recent excessive intake of NSAIDs. The biggest study actually published in literature on endoscopic hemostasis with Hemospray is from Smith LA et al. on 63 patients with NVUGIB. There were 30 patients with bleeding ulcers and 33 with other NVUGIB pathology. Fifty-five (87%) patients were treated with Hemospray as monotherapy; 47 (85%) of them achieved primary hemostasis and rebleeding rate at 7 days was 15%. Primary hemostasis rate for Hemospray in patients with ulcer bleeds was 76%. Eight patients, who otherwise may have required either surgery or interventional radiology, were treated with Hemospray as second-line therapy after failure of other endoscopic treatments, all of whom achieved hemostasis following the adjunct of Hemospray [34]. Hemostasis failure and rebleeding rate are major in Forrest high-risk stigma, and for these reasons it is still necessary to find new endoscopic methods to treat these kinds of active ulcer bleeding and reduce related mortality. Nowadays, only few studies are published in literature on the efficacy of Hemospray in NVUGIB. Sung et al. [9] conducted a pilot study to evaluate the hemostatic efficacy of Hemospray in spurting and oozing ulcer bleeding. They enrolled 20 patients with active ulcer bleeding (19 F Ib and 1 F Ia) who were treated with one or two application of Hemospray. In case of failure of hemostasis, a traditional endoscopic
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approach was then performed. They obtained an initial successful hemostasis of 95% and a permanent hemostasis in 89.5% while recurrent bleeding was observed in two patients (10.5%). Results of this study are slightly better than ours, though we have enrolled a greater number of F Ia ulcer bleeding. Holster et al. [35] performed a study to assess Hemospray treatment outcome in patients on antithrombotic therapy (ATT), compared with patients not receiving such treatment at time of GI bleeding. UIGB in patients on ATT can be hard to treat with current endoscopic modalities and therefore novel approach should be evaluated. They enrolled 16 patients with UGIB of which 9 were due to peptic ulcer bleeding (4 F Ia and 5 F Ib). Eight patients were on ATT and, in this subgroup, immediate hemostasis after Hemospray was 63% while in the nonantithrombotic group was 100%. Global successful hemostasis was obtained in 81% of patients. Rebleeding rate was 38% in antithrombotic group and 25% in the whole number of patients was 31%. Sometimes successful hemostasis can be technically difficult to achieve because of large dimension or particular position of the ulcer. In these circumstances, Hemospray could be considered the ideal hemostatic endoscopic agent because it does not require a direct contact with the bleeding site. Hemospray can be used as monotherapy or in combination with other endoscopic treatment. To date, there are no definite indications for its use as monotherapy or in combination, but according to our experience, we can say that in small size F1a bleeding lesions, Hemospray in monotherapy is less effective. In conclusion, Hemospray appears to be an effective hemostatic therapy for bleeding ulcers F1a and 1b. Additional prospective studies are needed to further validate these findings. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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