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Endoscopic sclerosis of experimental esophageal varices in dogs
Endoscopic sclerosis of experimental esophageal varices in dogs
Choichi Sugawa, Yasushi Okumura, Charles E. Lucas, Alexander J. Walt,
MD MD MD MD
Detroit, Michigan
An experiment was designed to develop in dogs an appropriate model for producing esophageal varices and to study the effectiveness of endoscopic sclerosing of such varices. Upper esophageal (downhill> varices were successfully made in 11 dogs by partially ligating both the superior vena cava and azygous vein. Four dogs had peroral fiberoptic injections of 5% sodium morrhuate into proven varices prior to sacrifice. Lower esophageal varices were made successfully in 5 dogs by multiple intra-abdominal systemic portal venous interruption plus creation of a splenic arteriovenous shunt. These dogs were followed by weekly endoscopy previous to variceal injection at 4 to 8 weeks. Varices not sclerosed were patent at necropsy; all endoscopically sclerosed varices showed thrombosis, perivenous fibrosis, and thickening of the intima at necropsy. Three dogs with varices developed superficial ulcers at the site of injection. Observations were made of the effect of injecting dilated superficial epigastric veins. This study confirms that fiberoptic endoscopic sclerosis of esophageal varices in experienced hands is a safe, reliable, and simple technique of thrombosing esophageal varices. The application of this technique to the severely ill patient with bleeding varices is supported by these experiments. Endoscopic control of bleeding esophageal varices by the injection of a sclerosing agent has clinical appeal in view of the high mortality of portacaval shunt. The methodology, complications, and effectiveness of this modality of treatment needs further elucidation. The present study was designed: (1) to develop, in dogs, an appropriate model for producing esophageal varices; and (2) to study the effectiveness of endoscopic sclerosing of such varices. EXPERIMENTAL METHODS I. Upper Esophageal Varices. Thirty-five dogs weighing an average of 21 kg were anesthetized with intravenous pentobarbital, intubated, and ventilated. A right lateral thoracotomy through the fourth intercostal space was made. Both the superior vena cava and the azygous vein were dissected free above and below their confluence. The azygous vein was doubly ligated. The superior vena cava, superior to its junction with the azygous vein, was constricted to approximately 20 mm circumference in 10 dogs (Group A), to 10 mm in 20 dogs (Group B), and completely in 5 dogs (Group 0. The chest was closed, and the lungs were inflated. Twenty-two of the 35 dogs survived (8 in Group A, 14 in Group B, and 0 in Group 0. Those 22 surviving dogs were studied at 2-week intervals under general anesthesia by fiberoptic endoscopy to determine the extent of esophageal varices. II. Lower Esophageal Varices. Lower esphageal varices were made by a 2-stage operation.' The first stage consisted of splenectomy, distal pancreatectomy, omentectomy (greater and lesser), division of the right gastroepiploic veins, creation of a splenic arteriovenous fistula, and partial ligation of the splenic vein at its junction with the superior mesenteric vein raising splenic vein pressure to 40 cm H20. The splenic vein
was completely occluded at the second operation 1 month later. Nine of 15 dogs survived the first operation, whereas 7 dogs survived 2 weeks after the second operation and were available for fiberoptic esophagoscopy. III. Endoscopic Sclerosing Technique. Sodium morrhuate (5%) was used as the sclerosing agent. A dosage of 2 ml was injected into 2 sites ofthe esophagus and stomach in 5 dogs by needle (Olympus) through the biopsy channel of the Olympus TGF-2D. IV. Injection Into the Experimentally Produced Esophageal Varices. Four dogs in the (I) upper esophageal varices group, and 3 dogs in the (II) lower esophageal varices group had injections of 5% sodium morrhuate into the varices by needle through the biopsy channel of the TGF-2D endoscope between 4 and 8 weeks after surgery. Injection was repeated on an average of 3 ti mes for about a month and endoscopic examination was done at weekly intervals. V. Injections Into the Experimentally Produced Superficial Epigastric Veins. Injections were made into and around the multiple prominent superficial epigastric veins of 4 dogs of Group I. Two incisions, measuring 1 and 4 mm in length, respectively, were made on the 8 mm vein using a knife and attempts were made, by injection, to stop the active bleeding. RESULTS I. Upper Esophageal Varices. The dogs that survived the initial surgery in Groups A and B usually regained their strength and activity within 2 weeks. Esophageal varices were observed at interval fiberoptic esophagoscopy in 11 of the 22 surviving dogs; including 2 of 8 surviving dogs in Group A and 9 of 14 surviving dogs in Group B. The varices developed in the upper thi rd ofthe esophagus in a submucosal position and were easily visible (Figure 1A). Histological examination confirmed the presence of enlarged submucosal esophageal veins
From the Department of Surgery, Wayne State University, Detroit, Michigan. Supported by the Detroit General Hospital Research Corporation, Detroit, Michigan 48226. Reprint requests: Choichi Sugawa, MD, Wayne State University Department of Surgery, 540 E. Canfield Avenue, Detroit, Michigan 48201.
114
GASTROINTESTINAL ENDOSCOPY
(Figure 1B). The varices persisted throughout the period of
study and were still present at necropsy autopsy (4 to 8 weeks). II. Lower Esophageal Varices. Esophageal varices were observed in 5 of 7 surviving dogs. The varices developed in the lower third of the esophagus in a submucosal position and were easi Iy visible (Figure 1C). Histological exami nation confirmed the presence of enlarged submucosal esophageal veins (Figure 10). The varices persisted throughout the period of study and were still present at necropsy (at 8 weeks). 1/1. Endoscopic Sclerosing Technique. The site of injection is usually recognized as mucosal swelling; this subsides in a week. A superficial ulcer developed in 2 of 10 injection sites of 2 ml in the esophagus. No ulcer developed when 0.5 or 1 ml were injected. An ulcer developed in 3 of 10 stomachs where 2 ml and 1 ml were injected. The ulcers healed in about 3 weeks. Histological study showed acute coagulative necrosis with severe acute inflammation at the site of injection. A thrombosed vein could be found in the submucosa of the stomach (Figure 2A). IV. Injection Into the Experimentally Produced Esophageal Varices. Seven dogs, from both groups, were injected. As confirmed by endoscopic examination, the varices disappeared in all. Histology showed inflammatory change at the site of injection with extremely thickened venous walls (Figure 2B). V. Injection Into the Experimentally Produced Superficial Epigastric Veins. Two ml of sodium morrhuate were injected into four veins (4, 6, and 8 mm in diameter). The results are shown in Table I. The 4 veins, 4 mm in diameter, were thrombosed by 1 intravenous or perivenous injection of 2 ml sodium morrhuate. Two ulcers developed after perivenous injection. Three of the 4 veins, 6 mm in diameter, were
Table I.
Results of 2 ml injection into superficial epigastric veins. 4(mm)
diameter 6 mm
10 mm
intravenous 4(4) 4(3) 4(2) 4(1 )[2] perivenous 4(4)[2] 4(3)[3] Numbers in parenthesis () are thrombosed veins; numbers in brackets [1 signify ulcers at the sites of injection.
thrombosed by an IV or perivenous injection, respectively. Three ulcers developed after perivenous injection. Only 1 of the 4 veins, 10 mm in diameter, was thrombosed by 2 intravascular injections of 2 ml sodium morrhuate at intervals of 1 week. Superficial ulcers were found in nearly half of the injection sites. The four veins, 4 mm in diameter, were thrombosed after a single intravenous injection of 1 ml of sodium morrhuate. Three of the four veins (4 mm in diameter) were thrombosed after perivascular injection of 1 ml sodium morrhuate. One ulcer developed after 1 ml perivascular injection. Bleeding caused by paired 1 mm incisions could be controlled by perivascular injection, but bleeding caused by paired 4 mm incisions could not be controlled by injection and local pressure was applied to stop vigorous hemorrhage. Histological section of injected veins showed markedly dilated veins with organized thrombus (Figure 2C). Histological section of perivascular injection showed extensive coagulation necrosis with severe acute inflammation. The venous lumen was filled with organized thrombus (Figure 20). DISCUSSION Hemorrhage from gastroesophageal varices is usually lethal. Several therapeutic measures have been used to stop variceal hemorrhage. These include: (1) gastric lavage
Figure 1. A, endoscopic view of varices experimentally produced in the upper third of the esophagus of the dog; B, enlarged submucosal esophageal veins; C, varices developed in the lower third of the esophagus; D, enlarged submucosal esophageal vein. VOLUME 24, NO.3, 1978
115
and decompressions, (2) intravenous or intra-arterial pitressin infusion, (3) balloon tamponade, (4) operative decompression, (5) oversewing of varices, and (6) injection sclerotherapy, No single treatment modality has achieved uniform success. 2 Operative intervention is particularly hazardous since these patients are extremely poor operative risks. Injection sclerotherapy of bleeding esophageal varices has the attraction of being a lesser surgical procedure. Though encouraging results have been reported from a few centers,3-7 the technique has only recently been more widely adopted. The advent of the fiberesophagoscope permits injection under local anesthesia, thereby decreasing the complication rate. S The injection may be repeated at intervals in an attempt to prevent further episodes of hemorrhage. This may prove more successful than therapeutic portacaval shunts done either as an emergency or electively.The indications for sclerosing injection given by several authors are: (1) bleeding esophageal varices, when a portacaval shunt is contraindicated because of very poor liver function; (2) prehepatic portal vein thrombosis; (3) thrombosed anastomosis between the portal and caval system; (4) bleeding varices in children; (5) solitary varicose nodule; and (6) recently bleeding esophagael varices. Hunt' described, in patients coming to necropsy after injection therapy, the thrombosis of the veins and perivenous fibrosis, thickening of the intima, and the organization of the thrombus. We observed the same kind of histological changes and coagulative necrosis of the tissue in our experiments, but no bleeding resulted from those changes. Other complications of sclerosing therapy include bleeding from gastric varices al)d necrosis of the esophagus. 6 Attempts have been previously made to develop varices in the dog. Tamiya and ThaI' produced large esophageal varices in the lower esophagus of the dog by a 2-stage operation. Laufman and Raach'o succeeded in producing esophageal varices in Macacca Rhesus monkeys by 2-stage venous ligation technique. The varices developed in the lower esophagus. The experimental production of the upper esophageal varices by thoracotomy and partial venous interruption is a new, simple, and effective l-stage technique. This experimental dog model can be used to find an ideal sclerosing agent or therapy for esophageal varices.
c REFERENCES 1. TAMIYA T, THAL PA: Esophageal varices produced experimentally in the
D ~"'~ 'k
,_
Figure 2. Following sclerosing injection: A, thrombosed vein was found in the submucosa of the stomach; B, extremely thickened venous wall with fibrosis; D, markedly dilated vein with organized thrombus (the defect was artifact); D, venous lumen was filled with organized thrombus,
dog. Surg Gynecol Obstet 111:147, 1960 2. CONN HO, RAMSBY GR, STORER EH, MUTCH NICK MG, JOSHI PH, PHILLIPS MM, COHEN GA, FIELDS GN, PETROSKI D: Intra-arterial vasopressin in the treatment of upper gastrointestinal hemorrhage: a prospective controlled clinical trial. Gastroenterology 68:211, 1975 3. HUNT PS, JOHNSTON GW, RODGERS HW: The emergency management of bleeding esophageal varices with sclerosing injections. Br! Surg 56:305, 1969 4. DENCK H: Endo-esophageal sclerotherapy of bleeding esophageal varices.! Cardiovasc Surg 12:146, 1971 5. JOHNSTON GW, RODGES HW: A review of 15 years' experience in the use of sclerotherapy in the control of acute hemorrhage from esophageal varices. Br ! Surg 60: 797, 1973 6. RASCHKE E, PAQUET KT: Management of hemorrhage from esophageal varices usingesophagascopic sclerosing methods.AnnSurg 177: 102,1973 7. EDITORIAL: New measures for bleeding esophageal varices. Br Med ! 23:450, 1975 8. BARLEY ME, DAVISON jL: Modified esophagascope for injection esophageal varices. Br Med! 2:540, 1975 9. CONN HO: Therapeutic portacaval anastomosis: to shunt or not to shunt. Gastroenterology 67:1065,1974 10. LAUFMAN H, BERNHARD V, ROACH HD, CHAMPLAIN G: Experimental production of esophageal varices in the Macaca rhesus. Surg Gynecol Obstet 110:451, 1960
Choichi Sugawa, Yasushi Okumura, Charles E. Lucas, Alexander J. Walt,
MD MD MD MD
Detroit, Michigan
An experiment was designed to develop in dogs an appropriate model for producing esophageal varices and to study the effectiveness of endoscopic sclerosing of such varices. Upper esophageal (downhill> varices were successfully made in 11 dogs by partially ligating both the superior vena cava and azygous vein. Four dogs had peroral fiberoptic injections of 5% sodium morrhuate into proven varices prior to sacrifice. Lower esophageal varices were made successfully in 5 dogs by multiple intra-abdominal systemic portal venous interruption plus creation of a splenic arteriovenous shunt. These dogs were followed by weekly endoscopy previous to variceal injection at 4 to 8 weeks. Varices not sclerosed were patent at necropsy; all endoscopically sclerosed varices showed thrombosis, perivenous fibrosis, and thickening of the intima at necropsy. Three dogs with varices developed superficial ulcers at the site of injection. Observations were made of the effect of injecting dilated superficial epigastric veins. This study confirms that fiberoptic endoscopic sclerosis of esophageal varices in experienced hands is a safe, reliable, and simple technique of thrombosing esophageal varices. The application of this technique to the severely ill patient with bleeding varices is supported by these experiments. Endoscopic control of bleeding esophageal varices by the injection of a sclerosing agent has clinical appeal in view of the high mortality of portacaval shunt. The methodology, complications, and effectiveness of this modality of treatment needs further elucidation. The present study was designed: (1) to develop, in dogs, an appropriate model for producing esophageal varices; and (2) to study the effectiveness of endoscopic sclerosing of such varices. EXPERIMENTAL METHODS I. Upper Esophageal Varices. Thirty-five dogs weighing an average of 21 kg were anesthetized with intravenous pentobarbital, intubated, and ventilated. A right lateral thoracotomy through the fourth intercostal space was made. Both the superior vena cava and the azygous vein were dissected free above and below their confluence. The azygous vein was doubly ligated. The superior vena cava, superior to its junction with the azygous vein, was constricted to approximately 20 mm circumference in 10 dogs (Group A), to 10 mm in 20 dogs (Group B), and completely in 5 dogs (Group 0. The chest was closed, and the lungs were inflated. Twenty-two of the 35 dogs survived (8 in Group A, 14 in Group B, and 0 in Group 0. Those 22 surviving dogs were studied at 2-week intervals under general anesthesia by fiberoptic endoscopy to determine the extent of esophageal varices. II. Lower Esophageal Varices. Lower esphageal varices were made by a 2-stage operation.' The first stage consisted of splenectomy, distal pancreatectomy, omentectomy (greater and lesser), division of the right gastroepiploic veins, creation of a splenic arteriovenous fistula, and partial ligation of the splenic vein at its junction with the superior mesenteric vein raising splenic vein pressure to 40 cm H20. The splenic vein
was completely occluded at the second operation 1 month later. Nine of 15 dogs survived the first operation, whereas 7 dogs survived 2 weeks after the second operation and were available for fiberoptic esophagoscopy. III. Endoscopic Sclerosing Technique. Sodium morrhuate (5%) was used as the sclerosing agent. A dosage of 2 ml was injected into 2 sites ofthe esophagus and stomach in 5 dogs by needle (Olympus) through the biopsy channel of the Olympus TGF-2D. IV. Injection Into the Experimentally Produced Esophageal Varices. Four dogs in the (I) upper esophageal varices group, and 3 dogs in the (II) lower esophageal varices group had injections of 5% sodium morrhuate into the varices by needle through the biopsy channel of the TGF-2D endoscope between 4 and 8 weeks after surgery. Injection was repeated on an average of 3 ti mes for about a month and endoscopic examination was done at weekly intervals. V. Injections Into the Experimentally Produced Superficial Epigastric Veins. Injections were made into and around the multiple prominent superficial epigastric veins of 4 dogs of Group I. Two incisions, measuring 1 and 4 mm in length, respectively, were made on the 8 mm vein using a knife and attempts were made, by injection, to stop the active bleeding. RESULTS I. Upper Esophageal Varices. The dogs that survived the initial surgery in Groups A and B usually regained their strength and activity within 2 weeks. Esophageal varices were observed at interval fiberoptic esophagoscopy in 11 of the 22 surviving dogs; including 2 of 8 surviving dogs in Group A and 9 of 14 surviving dogs in Group B. The varices developed in the upper thi rd ofthe esophagus in a submucosal position and were easily visible (Figure 1A). Histological examination confirmed the presence of enlarged submucosal esophageal veins
From the Department of Surgery, Wayne State University, Detroit, Michigan. Supported by the Detroit General Hospital Research Corporation, Detroit, Michigan 48226. Reprint requests: Choichi Sugawa, MD, Wayne State University Department of Surgery, 540 E. Canfield Avenue, Detroit, Michigan 48201.
114
GASTROINTESTINAL ENDOSCOPY
(Figure 1B). The varices persisted throughout the period of
study and were still present at necropsy autopsy (4 to 8 weeks). II. Lower Esophageal Varices. Esophageal varices were observed in 5 of 7 surviving dogs. The varices developed in the lower third of the esophagus in a submucosal position and were easi Iy visible (Figure 1C). Histological exami nation confirmed the presence of enlarged submucosal esophageal veins (Figure 10). The varices persisted throughout the period of study and were still present at necropsy (at 8 weeks). 1/1. Endoscopic Sclerosing Technique. The site of injection is usually recognized as mucosal swelling; this subsides in a week. A superficial ulcer developed in 2 of 10 injection sites of 2 ml in the esophagus. No ulcer developed when 0.5 or 1 ml were injected. An ulcer developed in 3 of 10 stomachs where 2 ml and 1 ml were injected. The ulcers healed in about 3 weeks. Histological study showed acute coagulative necrosis with severe acute inflammation at the site of injection. A thrombosed vein could be found in the submucosa of the stomach (Figure 2A). IV. Injection Into the Experimentally Produced Esophageal Varices. Seven dogs, from both groups, were injected. As confirmed by endoscopic examination, the varices disappeared in all. Histology showed inflammatory change at the site of injection with extremely thickened venous walls (Figure 2B). V. Injection Into the Experimentally Produced Superficial Epigastric Veins. Two ml of sodium morrhuate were injected into four veins (4, 6, and 8 mm in diameter). The results are shown in Table I. The 4 veins, 4 mm in diameter, were thrombosed by 1 intravenous or perivenous injection of 2 ml sodium morrhuate. Two ulcers developed after perivenous injection. Three of the 4 veins, 6 mm in diameter, were
Table I.
Results of 2 ml injection into superficial epigastric veins. 4(mm)
diameter 6 mm
10 mm
intravenous 4(4) 4(3) 4(2) 4(1 )[2] perivenous 4(4)[2] 4(3)[3] Numbers in parenthesis () are thrombosed veins; numbers in brackets [1 signify ulcers at the sites of injection.
thrombosed by an IV or perivenous injection, respectively. Three ulcers developed after perivenous injection. Only 1 of the 4 veins, 10 mm in diameter, was thrombosed by 2 intravascular injections of 2 ml sodium morrhuate at intervals of 1 week. Superficial ulcers were found in nearly half of the injection sites. The four veins, 4 mm in diameter, were thrombosed after a single intravenous injection of 1 ml of sodium morrhuate. Three of the four veins (4 mm in diameter) were thrombosed after perivascular injection of 1 ml sodium morrhuate. One ulcer developed after 1 ml perivascular injection. Bleeding caused by paired 1 mm incisions could be controlled by perivascular injection, but bleeding caused by paired 4 mm incisions could not be controlled by injection and local pressure was applied to stop vigorous hemorrhage. Histological section of injected veins showed markedly dilated veins with organized thrombus (Figure 2C). Histological section of perivascular injection showed extensive coagulation necrosis with severe acute inflammation. The venous lumen was filled with organized thrombus (Figure 20). DISCUSSION Hemorrhage from gastroesophageal varices is usually lethal. Several therapeutic measures have been used to stop variceal hemorrhage. These include: (1) gastric lavage
Figure 1. A, endoscopic view of varices experimentally produced in the upper third of the esophagus of the dog; B, enlarged submucosal esophageal veins; C, varices developed in the lower third of the esophagus; D, enlarged submucosal esophageal vein. VOLUME 24, NO.3, 1978
115
and decompressions, (2) intravenous or intra-arterial pitressin infusion, (3) balloon tamponade, (4) operative decompression, (5) oversewing of varices, and (6) injection sclerotherapy, No single treatment modality has achieved uniform success. 2 Operative intervention is particularly hazardous since these patients are extremely poor operative risks. Injection sclerotherapy of bleeding esophageal varices has the attraction of being a lesser surgical procedure. Though encouraging results have been reported from a few centers,3-7 the technique has only recently been more widely adopted. The advent of the fiberesophagoscope permits injection under local anesthesia, thereby decreasing the complication rate. S The injection may be repeated at intervals in an attempt to prevent further episodes of hemorrhage. This may prove more successful than therapeutic portacaval shunts done either as an emergency or electively.The indications for sclerosing injection given by several authors are: (1) bleeding esophageal varices, when a portacaval shunt is contraindicated because of very poor liver function; (2) prehepatic portal vein thrombosis; (3) thrombosed anastomosis between the portal and caval system; (4) bleeding varices in children; (5) solitary varicose nodule; and (6) recently bleeding esophagael varices. Hunt' described, in patients coming to necropsy after injection therapy, the thrombosis of the veins and perivenous fibrosis, thickening of the intima, and the organization of the thrombus. We observed the same kind of histological changes and coagulative necrosis of the tissue in our experiments, but no bleeding resulted from those changes. Other complications of sclerosing therapy include bleeding from gastric varices al)d necrosis of the esophagus. 6 Attempts have been previously made to develop varices in the dog. Tamiya and ThaI' produced large esophageal varices in the lower esophagus of the dog by a 2-stage operation. Laufman and Raach'o succeeded in producing esophageal varices in Macacca Rhesus monkeys by 2-stage venous ligation technique. The varices developed in the lower esophagus. The experimental production of the upper esophageal varices by thoracotomy and partial venous interruption is a new, simple, and effective l-stage technique. This experimental dog model can be used to find an ideal sclerosing agent or therapy for esophageal varices.
c REFERENCES 1. TAMIYA T, THAL PA: Esophageal varices produced experimentally in the
D ~"'~ 'k
,_
Figure 2. Following sclerosing injection: A, thrombosed vein was found in the submucosa of the stomach; B, extremely thickened venous wall with fibrosis; D, markedly dilated vein with organized thrombus (the defect was artifact); D, venous lumen was filled with organized thrombus,
dog. Surg Gynecol Obstet 111:147, 1960 2. CONN HO, RAMSBY GR, STORER EH, MUTCH NICK MG, JOSHI PH, PHILLIPS MM, COHEN GA, FIELDS GN, PETROSKI D: Intra-arterial vasopressin in the treatment of upper gastrointestinal hemorrhage: a prospective controlled clinical trial. Gastroenterology 68:211, 1975 3. HUNT PS, JOHNSTON GW, RODGERS HW: The emergency management of bleeding esophageal varices with sclerosing injections. Br! Surg 56:305, 1969 4. DENCK H: Endo-esophageal sclerotherapy of bleeding esophageal varices.! Cardiovasc Surg 12:146, 1971 5. JOHNSTON GW, RODGES HW: A review of 15 years' experience in the use of sclerotherapy in the control of acute hemorrhage from esophageal varices. Br ! Surg 60: 797, 1973 6. RASCHKE E, PAQUET KT: Management of hemorrhage from esophageal varices usingesophagascopic sclerosing methods.AnnSurg 177: 102,1973 7. EDITORIAL: New measures for bleeding esophageal varices. Br Med ! 23:450, 1975 8. BARLEY ME, DAVISON jL: Modified esophagascope for injection esophageal varices. Br Med! 2:540, 1975 9. CONN HO: Therapeutic portacaval anastomosis: to shunt or not to shunt. Gastroenterology 67:1065,1974 10. LAUFMAN H, BERNHARD V, ROACH HD, CHAMPLAIN G: Experimental production of esophageal varices in the Macaca rhesus. Surg Gynecol Obstet 110:451, 1960