Controlled Trial of Y AG Laser Treatment of Upper Digestive Hemorrhage

GASTROENTEROLOGY 1982;83:410-6 Controlled Trial of Y AG Laser Treatment of Upper Digestive Hemorrhage P. RUTGEERTS, G. VANTRAPPEN, L. BROECKAERT, J. JANSSENS, G. COREMANS, K. GEBOES, and P. SCHURMANS Departments of Medicine and of Medical Research, University Hospitals of Leuven, Leuven, Belgium A trial of neodymium-yttrium-aluminum-garnet laser treatment was conducted in 152 patients with upper gastrointestinal hemorrhage. Laser photocoagulation was applied in 0.5- to l-s pulses of 55-80 W power. A first part of the trial studying patients with arterial bleeding was uncontrolled. Spurting arterial bleedings could be stopped in 87% of the 23 patients with acute arterial hemorrhage. The recurrence rate after endoscopic treatment of this type of bleeding was high (55%). The operation rate of 61% was, however, lower than the operative indications amounting to 95% in patients with arterial spurters admitted previously to our department. One hundred twenty-nine patients were included in a controlled randomized trial of laser photocoagulation. In 86 patients with active, nonspurting bleeding, the laser was significantly better (p < 0.001) at stopping the bleeding than conservative treatment in randomized controls, and there was a numerical although not significant reduction of the rate of bleeding recurrence and the necessity for surgery (both p < 0.1). In 43 patients with fresh stigmata of bleeding (i.e., fresh clot or visible vessel) laser treatment resulted in a numerical reduction in the rate of rebleeding and in the operative indications, but the difference did not reach statistical significance. The mortality rates were not influenced in any of the groups. The overall mortality rate of acute upper gastrointestinal hemorrhage amounts to approximately 10% (1), ranging from 3.8% to 17% in large series (2,3). The mortality of severe gastrointestinal bleeding in highrisk patients-e.g., patients with multiple internal diseases, poly traumatism, or extensive burns-is much higher (4). Upper gastrointestinal (GI) endos- Received July 29, 1981. Accepted April 2, 1982. Address requests for reprints to: Professor Dr. G. Vantrappen, Department of Internal Medicine, A.Z. St. Rafael, Kapucijnenvoer 35, B-3000 Leuven, Belgium. 1982 by the American Gastroenterological Association 0016-5085/82/080410-07$02.50 copy has not altered the mortality of upper digestive hemorrhage (5-7). Early endoscopy allows by its accurate diagnostic yield a better choice of appropriate treatment, because specific bleeding lesions or stigmata (8,9) can be identified that are associated with a high probability of recurrent or uncontrollable bleeding. Endoscopic hemostatic techniques (10) could eventually improve the outcome of GI bleeding. Laser treatment seems to be one of the most promising hemostatic methods. Experiments using the "ulcer model" (11) have shown that both the neodymi um-yttri um-aluminum -garnet (neodymium-y AG) laser (12-18) and the argon laser (14,15,19-21) can be used efficiently and safely to stop ulcer bleeding in animals. Although uncontrolled studies with lasers (12,22-24) showed high efficacy in stopping gastrointestinal bleeding in humans, only controlled randomized studies can elucidate the influence of laser treatment on the natural history, the morbidity, and the mortality of bleeding. An effective, lasting, and safe nonoperative form of therapy of GI bleeding should indeed result in a reduced mortality rate in patients that are at high operative risk, and it could also reduce the duration of hospital admissions for GI bleeding as well as the average cost. However, controlled data on the value of laser treatment are scarce (25-27). The aim of this study was to evaluate the efficacy and the safety of neodymium-yag laser photocoagulation to stop upper GI bleeding or to prevent recurrence of bleeding, or both, in order to reduce the operation and the mortality rate in patients with upper GI bleeding. Patients with arterial spurters were studied by an uncontrolled trial. The results of laser in patients with active nonspurting bleeding and inactive bleeding with fresh stigmata were evaluated by a controlled, randomized study. Methods All patients with upper digestive hemorrhage admitted to the GI unit of the University Hospital during the

August 1982 Y AG TREATMENT OF UPPER GI HEMORRHAGE 411 past 3 yr underwent a diagnostic endoscopy within the first 12 h of admission. Those patients in whom the bleeding lesions could be visualized and for whom laser therapy was technically possible were included in a prospective study. They were divided into three groups. Group 1 consisted of patients with spurting arterial bleeding. The study design was submitted to the ethical committee of the hospital. Aware of the excellent results by Kiefhaber et al. (22) in severe GI bleeding, we were not allowed to randomize severely ill patients with arterial spurters for treatment. The risk of prolonging the duration of the endoscopy for laser therapy under close monitoring was considered to be less than the risk of an eventual operation. The committee felt that significant results could be obtained in this group without randomization. Therefore, all patients with arterial bleeding were treated by laser. A randomized trial was conducted in patients with active, nonspurting bleeding and in patients with inactive bleeding with fresh stigmata. Group 2 consisted of 86 patients with active bleeding, in whom arterial spurting could not be visualized. The 43 patients of group 3 did not bleed actively at the time of diagnostic endoscopy, but they did present with a stigma of fresh bleeding, i.e., a red clot or a visible vessel in the base of the ulcer. Patients of groups 2 and 3 were treated at random either by laser or by conservative means. Inclusion in the study and randomization were carried out during the diagnostic endoscopy. When the lesion was visualized and laser treatment was possible, patients were assigned by chance to laser treatment or conservative treatment alone. When the lesions diagnosed at endoscopy met with the study criteria, a nurse selected a card in a sealed envelope out of a box containing 70 cards marked with A (laser) and 70 cards marked with B (control). The card was then removed from the box. Laser treatment was then performed or the endoscopy was ended. Although bleeding in patients of group 1 was always severe, the degree of bleeding in patients of groups 2 and 3 was labeled "severe" if the acute transfusion need exceeded 5 U of blood or if the patient was admitted in shock. Other bleedings were classified as "mild." Laser Apparatus A neodymium-yag-iaser was used (Medilas MBB). delivering a power of 90 W. In the first part of the study (inclusion of 68 patients), the triconial quartz Nath fiber (28), introduced into the small biopsy channel of a double-channel Olympus gastroscope TGF-2D (Olympus Corporation of America, New Hyde Park, N.Y.), was used for transmission of the laser power. In patients with very severe bleeding, a diagnostic upper GI endoscopy was performed under general anesthesia and intubation by means of a small-caliber scope, usually GIF-Q (Olympus), was immediately followed by the introduction of the largecaliber TGF-2D gastroscope (Olympus) for the therapeutic part of the treatment. A new flexible fiber with coaxial CO 2 jet became available later in the course of the study. This fiber can be introduced into any routine endoscope. For laser treatment, however, the double-channel Olympus gastroscope XGIF-2T was used, which is particularly suitable for operative endoscopy. This small-caliber scope was always used for the diagnostic as well as the therapeutic part of the endoscopy. Treatment Modalities Treatment modalities to achieve maximal efficacy and safety were derived from previous animal studies (17). The exact output of laser power at the top of the fiber delivered with different amperages was not constant, but depended on the status of the laser apparatus and the quality of the fiber. The laser power was measured before each laser application. In the beginning of the study, due to imperfect adjustment of the laser and the use of the Nath fiber (which has a limited efficacy of power transmission), a maximal power of 50-65 W was obtained at the top of the fiber and this power was used for laser therapy. With better adjustment of the laser and the use of the new coaxial CO 2 jet fiber, a laser power of 70-80 W was obtained and used for treatment. Short laser pulses of 0.5 s or 1 s were applied. The duration of the pulses was limited electronically. In order to minimize the risk for transmural injury, patients were only treated once. The lesions were cleaned by water. A low-pressure coaxial CO 2 jet (200 mll min) was used only to keep the fiber clear; a high-pressure CO 2 jet was not used. In patients with severe bleeding and in high-risk patients, intubation and general anesthesia were performed in order to prevent pulmonary complications by aspiration during the procedure. In most patients, stomach cleansing with ice-cold saline was carried out by means of a large-bore gastric tube (Rosch). Lesions Treated All lesions in the esophagus, stomach, and duodenum in reach of the endoscope were treated except for esophageal and fundic varices or diffuse hemorrhagic lesions of the stomach or esophagus. Follow-Up of the Patients The follow-up of the patients and the decision to operate were the responsibility of one physician not aware of the endoscopic maneuvers. The conservative management of treated and untreated patients after endoscopy was identical and consisted of blood transfusion, parenteral alimentation, cimetidine (200 mg intravenously every 6 h), and correction of coagulation disorders. After the endoscopy, a stomach tube was placed in every patient. Continued bleeding was assessed by aspiration of fresh blood or by unequivocal clinical signs of bleeding (e.g., in duodenal ulcer) over a 24-h period, necessitating continuous blood transfusion. Recurrent bleeding was defined as upper GI bleeding occurring between 1-7 days after the first bleeding episode, thus necessitating a new blood transfusion. Recurrence of bleeding was always objectivated by a new endoscopic examination or by surgery. The physician responsible for the management was informed about the findings of the second endoscopic examination

412 RUTGEERTS ET AL. GASTROENTEROLOGY Vol. 83, No.2 but not about the type of previous treatment. Every operative decision was individualized, but it was based on generally accepted criteria. Continued bleeding or recurrence of bleeding were considered sufficient cause for immediate surgery only if a transfusion of >4 U of blood in a 24-h period was necessary or if the patient presented cardiovascular collapse. All patients who died in the course of the study underwent a careful necropsy with special attention for the treated lesions. In the mortality rates, all causes of death occurring after treatment are included, although it is obvious that not all these deaths are hemorrhage related (e.g., peritonitis by shot wounds). Results Between July 1978 and August 1981, 338 patients were admitted for upper digestive hemorrhage. One hundred eighty-six of them were excluded from the trial because of the nature of the lesion they presented with, i.e., diffuse hemorrhagic gastritis or duodenitis (30), bleeding esophageal varices (65), and lesions without fresh stigmata of bleeding (63). In addition, 20 patients could not be treated because of technical defects in the laser apparatus (mostly during the initial part of the trial). Only 8 patients were excluded in spite of the presence of a suitable bleeding lesion in the duodenum; in these patients, either the site of hemorrhage could not be reached by the endoscope, or the bleeding was too severe to permit adequate cleansing of the stomach or duodenum. Ninety-four out of the 152 patients studied (62%) had underlying diseases. Cardiovascular disease was the main disease in 20%, hepatic or pancreatic disease in 22%, neurologic or psychiatric disease in 7%, neoplastic disease in 8%, chronic lung disease in 6%, burns or poly traumatism in 3%, hematologic disease in 2%, metabolic disease in 2%, and chronic inflammatory bowel disease in 0.7%. In 15% of the patients multiple diseases occurred together. Only 47% of all patients had a history of gastroduodenal disease; 18% had a history of previous hemorrhage. The results of treatment in the 152 patients are summarized below. Group 1 All 23 patients (16 males and 7 females; mean age 59 yr; range, 17-85 yr) presenting with spurting arterial bleeding were treated by laser. The bleeding ulcer was localized in the stomach in 13 patients and in the duodenum in 10 patients. In 20 patients (87%), the bleeding could be stopped by laser. On average, 30 pulses were applied (range, 6-60). The hemostasis was permanent in 9 of the 20 patients (45%) whereas 11 of the 20 patients (55%) had recurrent hemorrhage after an interval of 1-36 h (mean, 12 h). Fourteen of the 23 patients (61%) had to be operated on. The overall mortality in the group of arterial spurters amounted to 7 out of 23 (30%). The cause of death was uncontrollable recurrence of bleeding after surgery in 2 patients, uncontrollable shock in 1 patient, and renal and hepatic failure in a fourth patient (in whom the bleeding had been permanently stopped by laser). Other causes of death were hepatic encephalopathy in 1 patient, bronchopulmonary complications in 1 patient, and cardiac infarction in 1 patient. Five patients had taken antiinflammatory drugs; 9 patients had a decreased Quick test or thrombocyte count. In this group 74% of the patients (17) had underlying diseases. Patients Submitted to Randomization for Treatment Treated and nontreated groups were well matched as to the age of the patients, the severity of bleeding, the presence of underlying diseases, and the presence of factors predisposing to bleeding, i.e., coagulation disorders and the intake of antiinflammatory drugs (Table 1). Data on the bleeding sources in the different treatment groups are summarized in Table 2. Group 2 Eighty-six patients were included in this group. The results of the treatment are summarized in Table 3. In 46 patients, 70 actively bleeding lesions were treated by laser. In all 46 patients the bleeding was controlled by 2-35 laser pulses (mean, 14). The control group consisted of 40 patients in whom 60 lesions were left untreated. Significantly more patients continued to bleed in the non treated group than in the laser group and there was a numerical reduction of rebleeding after initial hemostasis as well as a reduction of the operation rate (both p < 0.1) by laser therapy. The overall mortality rate was identical in both groups. Causes of death in the laser group were: recurrence of bleeding after surgery (1 patient), shock lung (1 patient), peritonitis secondary to abdominal shot wounds (1 patient), cholangitis and sepsis (1 patient), and mesenteric infarction (1 patient). Causes of death in the control group were: uncontrollable bleeding (2 patients), complications after surgery (2 patients), septic shock (1 patient), and cerebrovascular accident (1 patient). It may be noted that three of the surgically treated ulcers in the control group showed an arterial pumper at operation, while at endoscopy only active nonspurting bleeding had been found. All patients on whom surgery was performed had presented with severe bleeding.

August 1982 YAG TREATMENT OF UPPER GI HEMORRHAGE 413 Table 1. Comparison of Treatment Groups Number enrolled Male/female Mean age Q Severe bleeding Antiinflammatory drugs or coagulation disorders Underlying diseases Q Age range given in parentheses. Group 2 Group 3 Laser Control Laser Control 46 40 17 26 28/18 22/18 5/12 14/12 63 (19-84) 54 (33-78) 59 (21-72) 62 (19-84) 20 (44%) 13 (32%) 14 (82%) 16 (62%) 24 (52%) 20 (50%) 5 (29%) 10 (38%) 29 (63%) 25 (62%) 10 (59%) 13 (50%) Group 3 Forty-three patients were included in this group. The results are summarized in Table 4. Seventeen lesions in 17 patients, were treated by laser. The lesions contained a visible vessel in 6 patients and a fresh clot in 11 patients. The number of laser pulses applied varied from 3 to 61 (mean, 24). In 3 patients arterial spurting occurred after the first laser pulse, but the bleeding could be controlled by continued laser therapy in 2 patients. In 1 patient the bleeding could not be controlled, and in 2 patients the bleeding recurred. In 26 patients, 26 lesions (Le., 4 visible vessels and 22 fresh clots) were left untreated. The recurrence rate of bleeding was reduced by laser therapy as well as the operative indications, although this reduction was insignificant. Overall mortality was insignificantly lower in the laser group. Causes of death in the laser group were: postoperative complications in 1 patient and exsanguination in 1 patient. Causes of death in the control group were: bleeding recurrence and shock in 2 patients, alcoholic encephalopathy in 1 patient, and cardiac infarction in 1 patient. At surgery, arterial spurters were found in 2 patients in whom bleeding recurred during or after laser treatment and in 4 patients of the control group. In this group, too, all patients that were operated upon had presented with severe bleeding. Complications Severe complications of laser treatment were not observed: in particular no free perforations occurred in the course of the study. Two patients, 1 with a duodenal ulcer and 1 with an antral ulcer, developed a discrete transient increase of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase after laser therapy. Pulmonary complications were avoided during endoscopy by tracheal intubation in severely bleeding patients and were not more frequent in the treated than the nontreated patients. Discussion The characteristics (29), clinical prognostic factors (30), and diagnostic role of endoscopy in upper GI bleeding (31) have now been well defined. The method or combinations of methods that are effective and safe to treat upper GI bleeding have yet to be determined. Among the methods investigated, laser photocoagulation seems to be the most promising for the treatment of nonvariceal bleeding. The aim of the present studies was to investigate the efficacy of the neodymium-y AG laser in the treatment of upper digestive, nonvariceal hemorrhage. Consequently, the only patients admitted to the Table 2. Bleeding Sources in Patients Randomized for Treatment Active bleeding Inactive bleeding (n = 86) (n = 43) Laser Control Laser Control Lesions Patients Lesions Patients Lesions Patients Lesions Patients Stomach ulcers or erosions 33 20 31 16 9 9 13 13 Duodenal ulcers or erosions 18 16 17 15 5 5 9 9 Mallory-Weiss tears 9 5 9 6 3 3 4 4 Esophageal ulcers 2 2 1 1 Stoma ulcers 2 2 1 1 Stomach angiomas 6 1 Stomach carcinoma 1 1 Total 70 46 60 40 17 17 26 26

414 RUTGEERTS ET AL. GASTROENTEROLOGY Vol. 83, No.2 Table 3. Results in Group 2Q Gastric and duodenal ulcerative lesions Laser Control p Laser No. of patients 38 32 8 Bleeding stopped 38 25 <0.005 8 Bleeding recurred 2/38 5/25 <0.1 1/8 Operation 1 4 <0.2 0 Overall mortality 6 5 0 Q Active, nonspurting bleeding. study were those in whom laser therapy was thought to be technically possible during diagnostic endoscopy. Treatment failures therefore were directly related to the inefficacy of laser photocoagulation and not to shortcomings of the endoscopic techniques, e.g., lesions that could not be approached due to severe bleeding or lesions that were out of reach of the endoscope. Such endoscopic failures occurred in 5% of the patients fulfilling the other inclusion criteria. This is in contrast with some other studies (25,26) in which randomization was carried out before endoscopy. The failure rate in these circumstances is a combination of endoscopic and laser failures. All failures in the present series were fundamental failures of the Y AG laser or of the modalities of its application. Only lesions that are known to be associated with a high incidence of continuing bleeding or recurrence of bleeding were selected for treatment, i.e., active (spurting or oozing) bleeding and lesions with fresh stigmata of bleeding. Patients with bleeding varices were electively treated by sclerotherapy. Patients with lesions without fresh stigmata of bleeding at diagnostic endoscopy were not included in the study. Recurrence occurred in 5 out of 63 patients (8%) of this group. Laser was not used when the bleeding was diffuse or when too many bleeding lesions were present (>10 patients). The patients of the present prospective study were divided into three treatment groups according to the findings of the diagnostic endoscopy. Patients in whom arterial spurting was seen at endoscopy were always treated by laser. Although the success rate of the laser in stopping arterial bleeding was high Table 4. Results in Group 3 Q Gastric and duodenal ulcerative lesions Laser Control No. of patients 14 22 Bleeding recurred 3 7 Operation 2 5 Overall mortality 2 3 Q Inactive bleeding with fresh stigmata. Other lesions Total Control p Laser Control p 8 46 40 6 46 (100%) 31 (77%) <0.001 1/6 3/46 (7%) 6/31 (20%) <0.1 1 1 (2%) 5 (13%) <0.1 1 6 (13%) 6 (15%) (87%), the recurrence rate of bleeding amounted to more than one-half of the successfully treated patients and 61% of the patients with arterial spurters that required surgery. Compared with patients with arterial spurters admitted to our department in the years preceding the use of the YAG laser, laser treatment resulted in a decrease from 95% to 61% in the indications for surgery. The mortality in this group was not influenced by laser treatment. The main problem in the endoscopic laser treatment of gastroduodenal arterial bleeding, therefore, is not the initial hemostasis, but rather the prevention of recurrent bleeding. Further studies are required to determine whether laser photocoagulation must be stopped as soon as the bleeding has stopped or whether additional laser pulses should be appliedwhich, however, may increase the risk of rebleeding during therapy and of perforation. Patients randomized for treatment had either active nonspurting bleeding lesions, or lesions with fresh stigmata that no longer bled at the time of endoscopy. The latter patients were included in the study because it has been shown that fresh stigmata of bleeding predict rebleeding (8) and that in the case of visible vessels, uncontrollable bleeding or recurrent bleeding may occur in 100% of the patients (9) and always necessitates an operative procedure. Although in patients with arterial bleeding (group 1) and with visible vessels or fresh clots (group 3) a single lesion was always identified as the cause of bleeding, in patients with active bleeding, multiple bleeding lesions were identified in 25% of the patients. This study showed clearly that laser photoco- Mallory-Weiss tears Total Laser Control Laser Control 3 4 17 26 0 1 3 (18%) 8 (31%) 0 1 2 (12%) 6 (23%) 0 1 2 (12%) 4 (15%)

August 1982 YAG TREATMENT OF UPPER GI HEMORRHAGE 415 agulation was significantly (p < 0.001) better at stopping the hemorrhage in patients with active nonspurting bleeding than conservative treatment alone. Moreover, laser treatment tended to reduce the rate of bleeding recurrence and the necessity for surgery in these patients. In patients with fresh stigmata of bleeding, laser treatment occasionally induced acute arterial bleeding (in 3 patients with visible vessels), perhaps due to the direct application of photocoagulation on the visible vessel. In 1 patient, the resulting bleeding could not be stopped. In this group, laser treatment reduced both the rate of rebleeding and the operative indications, although not significantly. Papp et al. (32) were able to show significant differences in rebleeding of visible vessels in a small number of patients using monopolar electrocoagulation. Vallon et al. (27) randomized 108 nonbleeding ulcers to prophylactic argon-laser photocoagulation or sham treatment. No differences were noted in the rate of rebleeding, operation, or mortality in these groups. Bown et al. (33) treated 19 patients with visible vessels by argon laser photocoagulation. The rate of rebleeding of 9 out of 19 was equal to the rate of reb lee ding in a control group (9 out of 20). Visible vessels as described by Griffith et al. (9) occurred in only 10 out of 338 (3%) diagnostic endoscopies for upper GI bleedings in the present series. It has been recognized for a long time that recurrent bleeding is often severe. In this study, 69% of the active, nonspurting lesions or of the lesions with fresh stigmata that rebled or continued to bleed turned out to have changed to spurting arterial hemorrhages when surgery had to be carried out for recurrence of bleeding. This finding suggests that the main problem in the endoscopic control of upper digestive hemorrhage lies in the treatment of arterial bleeding. In conclusion, the present studies show that YAGlaser photocoagulation effectively stops upper GI hemorrhage in 87%-100% of the patients. In active bleeding, the laser is efficient to stop the bleeding, and laser treatment tends to prevent recurrence of bleeding and to lower the operation rate. Applied as described in this paper, the laser is safe. The main problem still is the treatment of severe arterial bleeding. This treatment can be improved in several ways: (a) The endoscopic technique should be improved so that all lesions can be approached. (b) The efficacy of laser treatment could be enhanced by repeated treatment-which, however, increases the risk of transmural injury. (c) Identification of those arterial bleedings that are likely to recur after laser photocoagulation could lead to more selective and more elective surgery. 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