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1 First Department of Internal Medicine, Hiroshima University School of
Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
2 Present address: Department of Gastroenterology, Hiroshima Prefectural
Hospital 1-5-54 Ujina-Kanda, Minami-ku, Hiroshima 734-8530, Japan.
3 Department of Clinical Radiology, Hiroshima University School of Medicine,
Hiroshima 734-8551, Japan.
4 Department of Radiology, Hiroshima University School of Medicine, Hiroshima
734-8551, Japan.
Received June 13, 2001;
accepted after revision November 20, 2001.
Address correspondence to M. Kitamoto.
Abstract
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SUBJECTS AND METHODS. Between December 1994 and February 2001, 24 consecutive patients with hemorrhage from gastric fundal varices were enrolled in this study. Balloon-occluded retrograde transvenous obliteration consisted of injecting 5% ethanolamine oleate iopamidol through the outflow vessels during balloon occlusion. The treatment was performed during acute bleeding in 11 patients and electively in 13 patients. Among those patients with acute bleeding, six were treated for temporary hemostasis with balloon tamponade, and five were treated endoscopically.
RESULTS. Cannulation into the outflow vessels was performed in 23 patients, but the balloon catheter could not be inserted in one patient who had inferior phrenic vein outflow. Complete success was obtained in 88% (21/24) of patients, and partial success was obtained in two patients. In nine of 11 patients with acute bleeding, complete success was achieved. Rebleeding from gastric varices was not observed in patients treated with complete success, whereas two patients treated partially rebled within 1 week of the treatment (rate of rebleeding, 9%). Eradication of gastric varices was obtained in all patients (n = 19) who were examined by endoscopy 3 months after the treatment. Eight patients experienced worsening of esophageal varices. These patients were treated endoscopically because of findings that suggested a risk of hemorrhage. The overall mortality rate was 4% (1/24). No damage to the kidney was observed, although 11 patients had macrohematuria.
CONCLUSION. Balloon-occluded retrograde transvenous obliteration followed by any hemostatic procedure might be effective for both prophylaxis of rebleeding and eradication of gastric fundal varices, even in urgent cases.
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The characteristics of the patients are shown in Table 1. The study included 18 men and six women with a mean age of 57 years. Among 23 patients with liver cirrhosis, the cause was viral liver cirrhosis in 13 patients (two patients were positive for hepatitis B surface antigen, and 11 patients were positive for antihepatitis C virus antibody), alcoholic liver cirrhosis in eight, primary biliary cirrhosis in one, and unknown cause in one (negative for viral markers). Four patients had complicating hepatocellular carcinoma with no tumor thrombosis in the main portal vein. Using Child's classification of esophageal varices [15], we categorized eight patients as grade A, 13 as grade B, and three as grade C. Serum creatinine levels varied from 0.51 to 1.4 mg/dL (average, 0.78 mg/dL).
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Endoscopic findings for varices were evaluated according to the general rules proposed by the Japanese Research Society for Portal Hypertension [16]. The location of gastric varices (Lg) was classified as adjacent to the cardiac ring (Lg-c), separated from the cardiac ring (Lg-f), and continuing from the cardiac ring to the gastric fundus (Lg-cf). The location of gastric varices was Lg-f in 22 patients and Lg-cf in the remaining two patients. The form of the varices was classified as small straight, enlarged tortuous, or large coil-shaped. The size of gastric fundal varices was enlarged tortuous in 11 patients and large coil-shaped in the remaining 13 patients. The size of esophageal varices was small straight in 12 patients, enlarged tortuous in three, and large coil-shaped in one. In the remaining eight patients, no esophageal varices were noted.
The clinical courses of patients from hospital admission to balloon-occluded retrograde transvenous obliteration and the details of the therapeutic results are shown in Figure 1. Seven patients had sustained hypovolemic shock on admission. They were initially treated with IV fluid administration, blood transfusion, and balloon tamponade and underwent endoscopic examination after improvement of their general condition. Eleven patients with bleeding signs were treated for temporary hemostasis with balloon tamponade (n = 6) and endoscopically (n = 5; two were treated with endoscopic injection sclerotherapy and three with endoscopic variceal ligation). Then all patients underwent contrast-enhanced CT to determine the presence of a gastrorenal shunt and, thereafter, to evaluate balloon-occluded retrograde transvenous obliteration under temporary hemostasis. In six patients, the presence of a gastrorenal shunt had already been confirmed by CT before hemorrhage from gastric varices. These patients were rapidly treated with balloon-occluded retrograde transvenous obliteration.
Balloon-Occluded Retrograde Transvenous Obliteration
Selective angiography of the celiac and superior mesenteric arteries was
performed before balloon-occluded retrograde transvenous obliteration to
evaluate portosystemic collaterals. Balloon-occluded retrograde transvenous
obliteration was performed by injecting 5% ethanolamine oleate iopamidol
(Oldamin; Grelan Pharmaceutical, Tokyo, Japan) through the outflow vessels
during balloon occlusion
[8,9,10,11,12,13,14].
A 6.5-French balloon catheter (Artec Balloon Catheter, B-RTO type I SML or
B-RTO type II SML; Create Medic, Tokyo, Japan) was inserted into the inferior
vena cava through the right femoral vein. The catheter was advanced into the
outflow vessels, such as the gastrorenal shunt or inferior phrenic vein. On
cannulation into the gastrorenal shunt, the balloon catheter was inserted into
the right atrium over a guidewire (Fig.
3A).
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After pulling out the guidewire, we reshaped the catheter by pushing on the interatrial septum (Fig. 3B). Clockwise rotation of the balloon catheter was performed until the tip of the catheter was twisted around the catheter itself (Fig. 3C). Then the balloon catheter was placed in the inferior vena cava, and the tip of the catheter was released by the insertion of a guidewire (Fig. 3D). The balloon catheter was inserted into the left renal vein cannulating the gastrorenal shunt (Fig. 3E). Blood flow directed into the inferior vena cava was blocked by inflating the balloon, and retrograde venography was conducted to determine the hemodynamics of gastric fundal varices and collaterals (Fig. 2C).
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Thereafter, 2.5-5 mL of 5% ethanolamine oleate iopamidol was intermittently injected into the gastric varices through the inflated balloon-occlusion catheter under fluoroscopy. When gastric varices were not visible or only partially opacified because blood flow was stealing through other collaterals, it was necessary to obliterate those vessels [9, 13, 14]. In patients in whom other collaterals were obviously present, the vessels should be obliterated with embolic coils. However, in patients with small vessels or in patients who could not be treated with coils, the use of 50% glucose or ethanol was indicated. These pretreatment occlusions of collaterals could limit the dosage of 5% ethanolamine oleate iopamidol. With or without these interventions, a microcatheter was introduced through a balloon catheter to the gastric varices, and selective administration of 5% ethanolamine oleate iopamidol was performed during balloon occlusion. When varices and inflow vessels could be shown in their entirety, injection was suspended (Fig. 2D).
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To avoid incomplete therapeutic efficacy and pulmonary infarction due to an unstable thrombus, we left the catheter in the vein with the balloon inflated for approximately 20 hr and removed it after retrograde venography (Fig. 2E). Human haptoglobin was prophylactically administered systemically IV before infusion of 5% ethanolamine oleate iopamidol. The therapeutic effects were evaluated by contrast-enhanced CT approximately 1 week after the treatment (Fig. 2F). Two radiologists interpreted the angiograms and retrograde venograms. Mortality was defined as any death occurring within 6 weeks after admission [17].
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Statistical Methods
The differences between the values of renal function and hepatic vein wedge
pressure before and after balloon-occluded retrograde transvenous obliteration
were analyzed using the Student's t test. The incidence of embolic
coils and the dose of 5% ethanolamine oleate iopamidol in relation to Hirota's
classification [13] were
statistically analyzed. The statistical difference was evaluated as
significant when the p value was less than 0.05 in all analyses.
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According to criteria for the difficulty of retrograde transvenous obliteration proposed by Hirota et al. [13], in which the degree of progression of gastric varices and collaterals was classified into five grades on the basis of the results of retrograde venography during balloon occlusion, four patients were classified as grade I, six as grade II, seven as grade III, and six as grade IV in the present study. With respect to patients who were treated completely, all four patients whose varices were considered to be grade I were treated without the use of embolic coils, and the average dose of 5% ethanolamine oleate iopamidol was 24 mL. In six grade II varices, embolic coils were necessary in one patient, and the average dose of the sclerosant was 18 mL. In six grade III varices, embolic coils were needed in two patients, and the average dose of the sclerosant was 29 mL. In five grade IV varices, embolic coils were needed in three patients, and the average dose of the sclerosant was 36 mL.
Other collaterals treated by embolic coils were the inferior phrenic vein (n = 4), the pericardiophrenic vein (n = 1), and the intercostal vein (n = 2). One patient was successfully treated with occlusion of both the gastrorenal shunt and the inferior phrenic vein by inflating two balloons.
Contrast-enhanced CT that was performed 1 week after treatment revealed complete thrombosis of gastric varices in 21 patients (Fig. 2F). These results showed good feasibility of the procedure. We could not place the embolic coils into other collaterals in two patients classified as grade IV, and only partial thrombosis was obtained with the use of 50% glucose and ethanol delivered through a microcatheter. These two partially treated patients could not receive further treatment because of the retrograde appearance of the left gastric vein or subintimal injury of the gastrorenal shunt. The reason for partial treatment in these two patients might be insufficient examination of portal collaterals because angiography was not performed as a result of the patients' urgent condition.
In the completely treated patients, the average dose of 5% ethanolamine oleate iopamidol was 25.7 mL. Although the use of embolic coils (p = 0.03) was related to the criteria proposed by Hirota et al. [13], the dose of 5% ethanolamine oleate iopamidol administered was not associated with the criteria. In the two completely treated patients mentioned previously, we successfully used a large amount of the sclerosant without severe complications. Pain in the epigastrium or in the back was observed in all patients, and fever was observed in six patients. These minor complications persisted for 2 days except in three patients who required an analgesic over 3 days. Macrohematuria was observed in 11 patients. One day after the procedure, a relatively high increase in serum lactic dehydrogenase occurred in all patients (average, 895 U/L), with a level greater than 1000 U/L of serum lactic dehydrogenase observed in one third of the patients, and a slight increase in serum aminotransferase level was observed in all the patients.
These results suggest that the occurrence of massive hemolysis was due to 5% ethanolamine oleate. However, the serum lactic dehydrogenase level returned to the baseline values within 2 weeks in almost all patients. The serum creatinine level varied from 0.47 to 1.6 mg/dL (average, 0.8 mg/dL) 1 day after the procedure and did not substantially change. Although a slight increase in the serum creatinine level was observed in three patients, measurements of renal function after the procedure returned to baseline values within a week in all patients. One patient developed ascites 3 days after the treatment, but the condition was successfully treated with furosemide.
We measured hepatic vein wedge pressure as portal pressure in five patients before and after the procedure. The hepatic vein wedge pressure before the procedure varied from 260 to 400 mm H2O (average, 310 mm H2O), and the hepatic vein wedge pressure after the procedure varied from 240 to 470 mm H2O (average, 334 mm H2O). The differences between the values before and after the procedure were not significant.
Rebleeding from gastric varices was not observed in patients who were treated with complete success, whereas two partially treated patients rebled within 1 week after the treatment (rate of rebleeding, 9%). Complete eradication of gastric varices was obtained in all the patients (n = 19) who were examined by endoscopy 3 months after the treatment (Fig. 2G). During the follow-up period (range, 3-64 months; mean, 21.2 months), no patients experienced bleeding from gastric varices, and reappearance of gastric varices was not observed by endoscopic examination in any patient. In patients who were treated with complete success, no deaths occured as a result of bleeding gastric varices, although four patients died of other diseases (Table 1). Among three patients who were treated unsuccessfully, one patient underwent Hassab's devascularization [18] 9 days after partial treatment, one patient with a Child's grade C classification and rebleeding shortly after the treatment died of liver failure, and one patient died of rebleeding from gastric fundal varices 1 year after the trial. The overall mortality rate was only 4% (1/24).
Worsening of esophageal varices was determined by endoscopic examination when the form of varices became enlarged tortuous or large coil-shaped or when a red spot was observed. In eight of 17 patients who had esophageal varices before the treatment, worsening of esophageal varices was observed. Two patients were prophylactically treated by endoscopy. In four patients, the worsened esophageal varices ruptured and were treated endoscopically. New esophageal varices did not appear in any patient who did not have esophageal varices before the treatment. No patient died from worsened esophageal varices.
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Moreover, because ethanolamine oleate promptly binds with albumin in the blood with loss of activity, the sclerosant is ideal for local obliteration of vessels [21]. However, ethanolamine oleaterelated complications have been reported, including severe renal dysfunction [22], pulmonary edema [23], disseminated intravascular coagulation [24], and anaphylactic reaction [13, 25]. Among these complications, renal dysfunction is not rare. As a result of intravascular hemolysis due to ethanolamine oleate, free hemoglobin is circulated and excreted by glomeruli, and the reabsorption of an excess amount of free hemoglobin may cause renal tubular dysfunction [22]. To avoid renal dysfunction, administration of haptoglobin before the procedure and a limited dose of ethanolamine oleate are necessary. Haptoglobin conjugates hemoglobin and may prevent renal tubular dysfunction [22].
With endoscopic sclerotherapy, the safe dose of ethanolamine oleate is reported to be less than 0.5 mL/kg in animal models [26] and less than 0.6 mL/kg in humans [27]. In the present study, no damage to the kidney was observed after the administration of haptoglobin, although half the treated patients had macrohematuria. Safety, and the complications our patients experienced, were similar to those reported previously.
In the treatment for bleeding gastric fundal varices, initial hemostasis and prevention of secondary bleeding are most important. Bleeding gastric varices are often treated with the administration of vasopressin and the use of balloon tamponade, but these treatments provide only a transient hemostatic effect. Although endoscopic sclerotherapy carries a considerable risk of prolonged bleeding from gastric ulceration at the injection site [1], endoscopic sclerotherapy using cyanoacrylate results in a more durable hemostasis [28, 29]. However, the use of cyanoacrylate is complicated. Moreover, endoscopic sclerotherapy using cyanoacrylate does not always successfully eradicate gastric varices, and it may cause unexpected complications such as cerebral infarction [30].
Surgical treatments such as Hassab's devascularization and transection have a limited role in the treatment of gastric varices because of hepatic dysfunction [18, 31]. Percutaneous transhepatic obliteration could obtain hemostasis, but rebleeding may occur [5]. It is likely that the antegrade procedure could obliterate inflow vessels but could not easily obliterate varices completely. The formation of new collateral inflow vessels may cause rebleeding from nonembolized varices. After the placement of a transjugular intrahepatic protosystemic shunt for gastric variceal hemorrhage, the rate of hemostasis is greater than 90%, and the incidence of rebleeding is approximately 30% [6, 7]. Transjugular intrahepatic portosystemic shunts may achieve hemostasis, but rebleeding rates are not satisfactory. Moreover, the procedure may induce hepatic encephalopathy or chronic hepatic failure [7]. On the other hand, balloon-occluded retrograde transvenous obliteration, as presented here, shows a high rate of hemostasis and a low rate of rebleeding. These findings would indicate that the retrograde procedure could easily obliterate whole varices in comparison with antegrade obliteration.
Indeed, many reports, including our series, showed that the rate of eradication for gastric varices is approximately 90% [8,9,10, 12]. Subsequently, portal pressure would increase because outflow vessels such as a gastrorenal shunt or an inferior phrenic vein were obliterated. Although balloon-occluded retrograde transvenous obliteration could worsen preexisting esophageal varices, patients who have no small varices have not developed worsened esophageal varices after the procedure. Thus, patients with small varices before retrograde obliteration must be carefully followed up with endoscopy.
The disadvantages associated with retrograde transvenous obliteration include an increase in portal pressure and the difficulty performing the procedure. It is likely that retrograde transvenous obliteration increases portal pressure because of obliteration of collateral veins connecting the portal venous system and systemic circulation. Indeed, portal pressure was reported to rise in all (seven) patients at least 1 week after the treatment [32], although in the present study, no difference was seen in the value of wedged hepatic venous pressure immediately before and 1 day after the treatment.
Many reports, including our series, showed a worsening of esophageal varices after the treatment [8,9,10, 12, 13]. However, the worsening of esophageal varices is offset by improvements in liver function and because portosystemic encephalopathy is well controlled after retrograde transvenous obliteration [13, 32, 33]. It is likely that the portal vein pressure of patients with worsened esophageal varices after the treatment may be high, because we studied patients with bleeding episodes from gastric varices. Moreover, the worsened esophageal varices could be successfully treated endoscopically.
Hirota et al. [13] showed the criteria for the difficulty of retrograde transvenous obliteration and that it is necessary to occlude small collaterals with an injection of ethanol or with embolic coils in half of the patients. Although we could achieve successful results using 50% glucose, ethanol, and embolic coils delivered through a microcatheter, we also experienced two technical failures. Moreover, it is not easy to perform this procedure without the presence of a shunt. In patients with inferior phrenic veins acting as outflow vessels, it was difficult to perform retrograde transvenous obliteration. We obtained a successful result in one patient. Because the prevalence of a shunt is reported to be approximately 90% in gastric fundal varices, such cases may be rare [34, 35]. Thus, the results presented here indicate that balloon-occluded retrograde transvenous obliteration of gastric varices is feasible.
Treatment of varices is focused on decreasing the risk of a first variceal hemorrhage, increasing survival from the acute bleeding, and preventing rebleeding. Balloon-occluded retrograde transvenous obliteration may perform all three functions. It remains unclear whether this procedure should be used prophylactically because of the high rate of worsened esophageal varices. In the present study, balloon-occluded retrograde transvenous obliteration proved feasible with low mortality and almost complete eradication of gastric fundal varices even in urgent conditions, although this aspect of the procedure was limited by the small number of patients. No panacea exists for portal hypertension except liver transplantation. For treatment of patients with hemorrhage from gastric varices, the usefulness of retrograde transvenous obliteration might overcome the risk of worsening of esophageal varices. Thus, balloon-occluded retrograde transvenous obliteration followed by any hemostatic procedure might be useful for gastric fundal varices even in urgent conditions.
Acknowledgments
We thank the radiographic staff for their cooperation and the nursing staff
for their treatment of the patients.
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