Zhiyang Wu, Wei Wu, Cheng Tao, Qin Liu, Wenchang Li, Qinbing Wang,Wei Huang, Junwei Gu, Xiaoyan Fei, Zhongmin Wang,＊＊, Xiaoyi Ding,＊
a Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
b Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
c Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, 15213, Pennsylvania, USA
d Shanghai Clinical Research Center Member for Interventional Medicine, China
Keywords:Gastric varices Gastrorenal shunt Balloon-occluded retrograde transvenous obliteration Sclerotherapy
ABSTRACT
Gastrointestinal bleeding is a common clinical symptom, among which esophageal and gastric variceal bleeding (EGVB) are the usual causes. Based on the location of the varix in the stomach and its correlation to esophageal varices, esophageal and gastric varices (GVs) are divided into gastroesophageal varices (GEVs) and isolated GVs (IGVs).1The risk of bleeding from GVs is relatively low (10%–36% of cases).2However, the bleeding is usually significant and the disease is severe.Common prevention and treatment methods for EGVB include non-selective beta-blocker therapy, digestive endoscopy therapy, surgical therapy, liver transplantation, and interventional therapy. Multiple studies have demonstrated that balloon-occluded retrograde transvenous obliteration (BRTO) achieved satisfactory bleeding control rates for IGVs.3,4Some reports showed that BRTO is more effective at preventing future variceal rebleeding than transjugular intrahepatic portosystemic shunt (TIPS)in some cases.5,6
The American Association for the Study of Liver Disease guidelines recommend secondary prevention of GV bleeding as an alternative to TIPS.7Some reports suggest that BRTO be considered a first-line modality for treating GVs with portal hypertension.8Although BRTO has been widely conducted abroad for many years,it is not commonly used in China.Ethanolamine oleate is a widely used sclerosant for BRTO sclerosis of varicose veins in Japan;however,it is unavailable in China.The effect of lauromacrogol sclerosant foam in our center as a substitute sclerosant for BRTO is summarized below.
2.1. Patients
This retrospective study was performed in accordance with medical ethics regulations, and our local institutional review board waived the requirement for informed consent. Written informed consent for the BRTO procedure was obtained from all patients or their families. Between January 2016 and December 2020, 31 consecutive patients with GVs underwent BRTO at our hospital.
The inclusion criteria were as follows1: diagnosis of gastrointestinal bleeding due to portal hypertension2; underwent preoperative gastroscopy to determine the variceal degree and classification;and3underwent portal vein computed tomography (CT) angiography to assess the presence of a gastrorenal venous shunt.
The exclusion criteria were as follows1:gastrointestinal bleeding with a non-portal hypertension cause such as peptic ulcers2; portal vein thrombosis3; uncontrolled esophageal variceal bleeding; and4serious impairment of important organs (e.g. heart, lung, kidney, and brain) or blood coagulation.
2.2. Preparation of sclerosant foam
The sclerosant foam was prepared by mixing iodinated oil (Yantai Luyin Pharmaceutical Co., Ltd., Shandong, China), lauromacrogol injection (Tianyu Pharmaceutical Co., Ltd., Shaanxi, China), and air at a 1:2:3 ratio, connecting two 50-mL syringes with three-way suction, and repeatedly mixing the solution 15 times.
2.3. BRTO procedures
Two interventional radiologists performed all of the BRTO procedures.The patients were placed in the supine position using the right femoral vein approach under local anesthesia. Guided by a 0.035-inch guide wire(Radifocus;Terumo,Tokyo,Japan),a 5F SIM II catheter(Boston Scientific Co., MA, USA) was selectively intubated to the gastrorenal shunt. Then,guided by a 0.035-inch stiff guidewire(Radiofocus;Terumo),a 7F occlusion balloon (Fogarty Thru-lumen embolectomy catheter; Edwards Lifesciences, CA, USA) was inserted into the gastrorenal shunt. For patients with a large inclination angle of the left renal vein toward the feet,an 8F introducer sheath (Flexor Check-Flo Introducer; Cook Medical, IN, USA)was exchanged before the Fogarty catheter was inserted. The gastric and renal shunts were entirely occluded by filling the balloon with a diluted contrast agent (iopamidol injection 370 mg I/mL; Shanghai Bracco Sine Pharmaceutical Co., Ltd., Shanghai, China), and retrograde transvenous venography was performed to evaluate the anatomy of the GVs and portosystemic collateral veins.If there were large draining collateral vessels,such as the inferior phrenic veins or pericardiophrenic veins, superselective catheterization with a microcatheter (Renegade STC-18; Boston Scientific)was performed into the collateral veins and then embolized with a microcoil(Interlock;Boston Scientific).
After the balloon inflation, repeat retrograde venography was performed to calculate the dosage of contrast agent required to reach the portal vein. Subsequently, sclerosant foam was slowly injected through the balloon catheter at the contrast agent dosage used in the previous venography.The filled balloon catheter was inflated overnight to occlude the gastric and renal shunts.The patients went back to the interventional operating room the next day,after which the remaining sclerosant foam was aspirated and the balloon slowly deflated.After manual angiography was performed to confirm complete occlusion of the varicose vein, the balloon catheter and long sheath were withdrawn under fluoroscopic guidance.A local compression dressing was applied at the puncture point of the right femoral vein.The patient"s vital signs were monitored during the procedure until the catheter was fully withdrawn.
2.4. Follow-up
Enhanced abdominal CT and endoscopy were performed at 1 month,6 months,and 1 year of follow-up.Varix sclerosis was defined as the absence of residual enhancement within the GVs on follow-up CT or disappearance of the GVs on endoscopy.Clinical success was defined as evidence that the varices did not recur and the absence of proof of rebleeding from the treated varices during follow-up.Complications were also recorded.
2.5. Statistical analyses
Descriptive and inferential statistics were used to analyze the data.The Kruskal-Wallis test was used to test the differences in variables before versus after the procedure because the data were not normally distributed. Statistical significance was set at P ＜0.05. The data were statistically analyzed, and the graphs were generated using GraphPad Prism 8(GraphPad Software,San Diego,CA).
3.1. Demographic data
Thirty-one patients (22 men, nine women; age range, 39–75 years)were enrolled. Liver cirrhosis was caused by hepatitis B virus (58.1%).The patients’demographic data are presented in Table 1.
3.2. Varicose vein classification
GEV and IGV cases were classified according to preoperative gastroscopy and abdominal contrast-enhanced CT findings.Two patients(6.5%) were classified as GEV1, four (12.9%) as GEV2, six (19.4%) as GEV3,and 19(61.3%)as IGV.All abdominal CT scans showed variablesized GVs with a gastrorenal shunt.
3.3. Procedural success rate
The BRTO procedure was successfully completed in 29 (93.5%) patients (Fig. 1). Among the two unsuccessful cases, one was due to too many collateral vessels, and the other was due to the excessively large gastrorenal shunt and no suitable balloon catheter. Both patients underwent TIPS successfully. Collateral vessels were embolized in 11 patients(35.5%)with microcoils before the injection of the lauromacrogol sclerosant foam. The dosage of the lauromacrogol sclerosant foam was 15–50 mL(mean,36.8±10.8 mL).
3.4. Complications
One patient was allergic to lauromacrogol injection as evidenced by an intraprocedural decreased heart rate and blood pressure, which recovered after epinephrine treatment. The procedure was successfullycompleted. A mild postoperative fever occurred in three patients. After symptomatic treatment with antipyretics, the body temperature normalized the next day. One patient had a grand mal seizure 5 h after the procedure, and the symptoms disappeared after medication. Reexamination of the liver function 1–3 days post-procedure showed no changes.No procedure-related deaths occurred.
Table 1 Patient characteristics.
Fig. 1. A 40-year-old man presented with hepatitis B cirrhosis and upper gastrointestinal bleeding. A. Enhanced abdominal computed tomography (CT) performed prior to balloon-occluded retrograde transvenous obliteration (BRTO) demonstrated isolated gastric varices in the stomach fundus (black star). B. Endoscopy performed before BRTO showed large isolated gastric varices at the fundus(black star).Red whale signs(black arrow)were visible on the varices,indicating a high risk of bleeding.C.The collateral vessels were embolized with microcoils(black arrow).D.Fluoroscopic image showing that the gastrorenal shunt was occluded by a Fogarty balloon catheter(black arrow)and the varices filled with sclerosant foam(black arrowheads).E.Enhanced CT performed 1 year after BRTO showing complete variceal regression. F. Endoscopy performed 2 years after BRTO showing nearly complete variceal regression with a few small emerging collaterals.
3.5. Postoperative follow-up
Hepatic functional reserve was assessed using the Child-Turcotte-Pugh score, and no significant differences before versus 6 months after the procedure were noted(p= 0.54)(Fig.2).
By December 31,2021,all patients were followed up for more than 1 year,with an average follow-up time of 508 days.Among the 29 patients who underwent successful BRTO, no rebleeding occurred in the treated varices during follow-up. CT portovenography or upper gastrointestinal endoscopy demonstrated complete resolution of the GVs in 27 patients(93.1%) (Fig. 1). One patient underwent endoscopic treatment for the development of high-risk esophageal varices.No further clinical episodes of upper gastrointestinal bleeding were noted. The other patient underwent TIPS for the aggravation of ascites.
BRTO is a common treatment method for GVs with gastrorenal shunts.Here we performed BRTO with materials available in China with a high success rate and a low rebleeding rate.
BRTO was first reported in 1984 by Olsen et al.9and is the first-line treatment for GVs with a gastrorenal shunt in Japan.2Indications include GVs with a left gastrorenal shunt and refractory hepatic encephalopathy.10Contraindications included severe coagulation disorders,regional portal hypertension due to splenic venous embolism,portal thrombosis,and uncontrolled esophageal venous bleeding.
Fig.2. Changes in hepatic function.Child-Turcotte-Pugh scores before and 1,3,and 6 months after BRTO were 6.5 ± 1.3, 7.0 ± 2.0, 6.4 ± 1.6, and 6.0 ± 1.1,respectively. The change was insignificant (p = 0.54).
Simmons II balloon catheters, cobra-shaped balloon catheters, and micro-balloon catheters are commonly used.3,11Ethanolamine oleate and sodium tetradecyl sulfate are widely used sclerosants. However, these products are not readily available in China. Lauromacrogol injection,with the molecular formula C12H25(OCH2CH2)nOH(n=9),was used in this study. It is often used to treat sclerosis in cases of vascular malformation. Its main side effects include fever, chest pain, decreased heart rate, stomach discomfort, and allergic reactions. In this study, lauromacrogol injection was mixed with iodized oil and air using the Tessari method12to form a sclerosant foam. Sclerosant foams have many advantages.First,the total sclerosant dosage was reduced.In this study,the average dosage of the lauromacrogol sclerosant foam was 36.8 mL.The sclerosant foam was prepared by mixing iodinated oil, lauromacrogol,and air at a 1:2:3 ratio.Even in patients with the highest foam dosage(50 mL),only 16.7 mL of lauromacrogol was injected.In addition,before balloon catheter removal, as much of the residual sclerosant as possible was withdrawn to avoid large amounts of embolism from entering the blood circulation.13Second, it is more effective to contact the vascular endothelium by increasing the surface area.Third,the foam could diffuse completely in varicose veins with better flowability. The results showed that the varicose veins were sclerotic in 93.1%of the cases during follow-up.
The success rate of BRTO is higher in patients with clearly defined gastrorenal shunts. In this study, 93.5% of the patients completed the BRTO procedure. Collateral vessels require embolization14or “downgrading”.15In our study, large collateral vessels were embolized using microcoils. No sclerosant leakage into the systemic circulation was observed. Balloon catheters of an appropriate diameter should be selected to avoid sclerosant backflow. Since only the Fogarty balloon catheter could be used in our hospital, occlusion failed in one patient with an excessively large gastrorenal shunt despite maximum balloon inflation. Of course, other methods such as coils could be used for the occlusion.The patient ultimately chose TIPS.
The complications of BRTO are primarily temporary and self-limited and mainly include upper abdominal and back pain, increased portal pressure,ascites,pleural effusion,pulmonary embolism,nausea,elevated blood pressure, and abnormal liver and kidney function.13BRTO had minimal effects on the liver function in this group of patients.Increased portal vein pressure after BRTO is likely to exacerbate esophageal varices,which requires attention.In the group of cases reported by Watanabe et al. esophageal varices worsened in 21.2% of patients.16Imai et al.reported that the cumulative exacerbation rates of esophageal varices at 1,3,and 5 years were 13%,20%,and 27%,respectively.17Elevation of the hepatic venous pressure gradient and spleen stiffness after BRTO might be useful for predicting the exacerbation of esophageal varices.18In this study, the postoperative esophageal varices of one patient progressed significantly and required endoscopic treatment.
BRTO was more effective than endoscopic cyanoacrylate injection in a randomized controlled trial to prevent GV rebleeding with similar complications and mortality rates.19BRTO has a favorable effect on long-term hepatic functional reserve.20Comparisons between BRTO and TIPS have always been controversial.A retrospective study by Lee et al.showed that cumulative rebleeding rates after BRTO (8.6% at 1 year;22.7%at 3 years)were significantly lower than those after TIPS(19.8%at 1 year;48.2%at 3 years;p=0.006).21A meta-analysis by Wang et al.showed that BRTO provided more benefits to patients with a higher overall survival rate and lower rebleeding rate.5In another retrospective study,BRTO appeared to be an effective method of treating isolated GVs with outcomes and complication rates similar to those of TIPS with a covered stent but with a lower hepatic encephalopathy rate.22In the present study, BRTO showed a sound clinical effect. Complete GV resolution was demonstrated in 93.1% of patients, and no further clinical episodes of upper gastrointestinal bleeding occurred. However, one patient underwent TIPS for ascites aggravation.However,owing to the lack of extensive sample data from prospective randomized controlled trials,the long-term efficacies of BRTO and TIPS require further data accumulation.
Another advantage of BRTO is that it is less expensive than TIPS.However, if too many collateral vessels require embolization, this advantage may not be obvious.In our study,the BRTO procedure failed in one patient because of the large number of collateral vessels. According to angiographic images, more than 20 controllable microcoils were needed to completely embolize all collateral vessels, which would lead to a high cost.Therefore,we discontinued the BRTO procedure and switched to TIPS treatment,which is relatively inexpensive.
The shortcomings of this study are that it was not a prospective controlled study,its sample size was small,and some patients were lost to regular follow-up during the coronavirus disease 2019 crisis.More cases are needed to accumulate data, especially when comparing BRTO and TIPS.
In conclusion,the current literature and our study suggest that BRTO is especially suitable for GVs with a gastrorenal shunt using lauromacrogol sclerosant foam. With fewer complications, satisfactory variceal sclerosis rates,a low rebleeding rate,and a relatively low cost,BRTO is worthy of application and promotion.
Funding
This work was funded by the National Natural Science Foundation of China (62173223), Shanghai Municipal Key Clinical Specialty (grant number shslczdzk06002), and Shanghai Clinical Research Center for Interventional Medicine(19MC1910300).
Declarations
This retrospective study was performed in accordance with the medical ethics regulations.Written informed consent was obtained from all participants. The ethics committee approved all experimental protocols of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.
Each author"s degrees
Zhiyuan Wu, Wei Wu, Cheng Tao, Qin Liu, Wenchang Li, Qinbing Wang, Wei Huang, Junwei Gu, Xiaoyan Fei, Zhongmin Wang, Xiaoyi Ding.
Declaration of competing interest
The authors declare that they have no competing interests.