EUS-Guided Cyanoacrylate Injection Versus Standard Endoscopic Technique in the Obturation of High Risk Gastric Varices
Phase: NA
Conditions: Gastric Varix
Sponsor: Mansoura University

 
 
 
 
 
EUS–guided Cyanoacrylate injection versus standard 
endoscopic technique in the obturation of high risk 
gastric varices 
 
Thesis 
 
Submitted for partial fulfillment of MD Degree in Hepatology 
and Gastroenterology 
By 
Fady Sabry Karam Mikhael 
M.B.B.CH, MSC, Ass. Lecturer of Internal Medicine 
(Hepatology and Gastroenterology unit)  
Faculty of Medicine - Mansoura University 
Supervised by 
Prof. Seham Mohamed Seif 
Professor of Internal Medicine-Hepatology and 
Gastroenterology 
Faculty of Medicine, Mansoura University 
Prof. Ayman Abd Alghafar Aldesoky 
Professor of Internal Medicine-Hepatology and 
Gastroenterology 
Faculty of Medicine, Mansoura University 
Ass. Prof. Hazem Hakim Almenshawy 
Associate Professor of Internal Medicine-Hepatology and 
Gastroenterology 
Faculty of Medicine, Mansoura University 
Lecturer: Ahmed Youssef Altonbary 
Lecturer of Hepatology and Gastroenterology 
Faculty of Medicine, Mansoura University 
2019  
 
Mansoura University            
Faculty of Medicine 
Internal Medicine Department 

Protocol of MD Thesis 
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Introduction 
 
         Gastric varices occur in around 20% of patients with portal 
hypertension, mostly secondary to liver cirrhosis. Although they bleed less 
frequently than oesophageal varices, gastric variceal bleeding tends to be 
more severe with reported higher mortality of approximately 45% (Wani et 
al., 2015). High risk gastric varices include presence of any of the following 
risk factors (Triantafyllou and Stanley, 2014): 
 Location of gastric varices (IGV1>GOV2>GOV1). 
 Size of fundal varices >10 mm. 
 Severity of liver failure (Child class C>B>A). 
 Endoscopic presence of variceal red spots. 
        Standard endoscopic management of  gastric varices is endoscopic 
intravariceal cyanoacrylate (CYA) injection for treatment of acute bleeding, 
as well as for secondary prophylaxis (Al-Hillawi et al., 2016). 
Endoscopic variceal obliteration (EVO) by direct endoscopic 
injection (DEI) using tissue adhesives like glue, CYA or histoacryl has 
provided a positive direction to management of GVs. CYA is a polymer 
which upon coming in contact with blood polymerizes instantly leading to 
obliteration of varices. It is called “obliteration” and not “eradication” since 
the varices may be still visible post treatment. EVO with N-butyl-2-
cyanoacrylate has been the advocated first-line method in managing the 
gastric varices especially fundic varices (Girotra, 2014). 
EVO  by DEI using CYA demonstrated higher hemostasis and lower 
bleeding rates compared to band ligation or sclerotherapy. Nevertheless, 
CYA treatment is known to be associated with significant adverse events like 
para-variceal injection, hemorrhage from post injection ulcer, needle 
sticking in the varix, intra-peritoneal injection leading to peritonitis  and 
adherence of the glue to the endoscope, fever, embolization into the renal 
vein, IVC, pulmonary or systemic vessels.  (Belletrutti et al., 2008). 

Protocol of MD Thesis 
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Pulmonary embolism due to CYA therapy is a serious complication 
and sometimes fatal. Pulmonary embolism appears to be more common in 
patients receiving a higher volume of cyanoacrylate during the injection 
procedure (Hwang et al., 2001). 
In recent years, the role of endoscopic ultrasound (EUS) has expanded 
rapidly into the therapeutic arena. EUS offers unique access to abdominal 
arterial and venous vasculature that until now has only been accessible to 
surgeons and/or interventional radiologists. This has had the most clinical 
impact on the treatment of gastroesophageal varices, where EUS may play a 
role both in the acute and elective management and can deliver therapy in 
the form of glue injection, endovascular coil placement or a combination of 
the two (Hall et al., 2017). 
EUS enables an assessment using Doppler to confirm vessel 
obliteration after treatment. However, targeting the perforating feeder vessel 
rather than the varix lumen itself may theoretically minimize the amount of 
CYA needed to achieve obliteration of GVs and thereby reduce the risk of 
embolization (Wang et al., 2016).  
Romero‑Castro et al. assessed the efficacy of EUS‑guided CYA 
injection at the entrance of the perforating veins to obtain variceal 
obliteration in five consecutive GV patients. They thought that EUS-guided 
CYA injection at the perforating veins of GV would be the optimal place to 
do so. This produces the maximal blood flow blockage of the inflow vein 
with lower amounts of CYA used and avoid either more punctures or more 
amounts of CYA necessary to fill the varix from the inflow to the outflow 
veins (Romero-Castro et al., 2007). 
To the best of our knowledge, no studies in the literature compared 
standard DEI to EUS guided CYA injection into perforating veins in high 
risk gastric varices which represents a significant clinical challenge as it 
requires injection of large amount of CYA & multiple sessions which is 
associated with high incidence of complications. 

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Aim of work 
 
 
 
         The aim of present study is to compare the efficacy & safety of EUS-
guided CYA injection at the entrance of the varix or the perforating veins 
versus DEI of CYA in treatment of high risk gastric varices.  
 
 

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Patients & Methods 
 
1. Study design & Characteristics: 
A single-centre, pilot randomized trial study with two arms; will be 
carried on patients over 1 year study period starting from June 2019 to June 
2020 at the EUS Unit of the Department of Gastroenterology at Mansoura 
Specialized Medical Hospital, Mansoura University (Egypt). 
2. Patients: 
A total of 42 patients will be included, GVs will be classified according to 
the Sarin and Kumar classification (Sarin and Kumar, 1989) into GOV II 
or IGV I with recently bleeding GV & high-risk GV (defined by Baveno VI 
consensus for primary prophylaxis). After obtaining consent, eligible patients 
will be randomized in 2 groups using computer-generated random number 
sequences using excel software in concealed envelopes with block 
randomization design.  Group I will undergo EUS-guided CYA injection at 
entrance of perforator veins. Group II will undergo DEI of CYA. 
i. 
Inclusion criteria: 
 Above 18 years old patients 
 High risk GOV II and IGV I varices (>10 mm) on initial standard 
diagnostic upper endoscopy 
 Recent bleeding and primary prophylaxis 
 Patients who are unable or unwilling to undergo alternative 
therapies for GV [such as transjugular intrahepatic portosystemic 
shunts (TIPS) or surgery], or prior TIPS had failed. 
 
ii. 
Exclusion criteria : 
 Inability to give informed consent for the procedure. 
 Concurrent hepatorenal syndrome and/or multiorgan failure. 
 Presence of HCC &/or portal vein thrombosis. 
 Previous endoscopic treatment for GVs. 

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 Platelet count less than 50,000/ml or International Normalized 
Rate (INR) >2 
 Esophageal stricture 
 Previous esophageal or gastric surgery. 
 Pregnancy. 
 
iii. 
Sample size 
Sample size was calculated by PASS software for Windows (version 
11.0.8). 
The reported rate of obliteration of fundic varices after CA injection 
is high (90%) in control group (Martínez-González et al., 2015), and we 
hypothesized this rate to be 99% in EUS group. 
Group sample sizes of 201 in group one (EUS group) and 201 in group 
two (control group) achieve 99% power to detect a difference between the 
group proportions of 0.1000. The proportion in group one (the treatment 
group) is assumed to be 0.9000 under the null hypothesis and 1.0000 under 
the alternative hypothesis. The proportion in group two (the control group) 
is 0.9000. The test statistic used is the one-sided Z test with pooled variance. 
The significance level of the test was targeted at 0.0100 . 
According to Connelly (2008), a pilot study sample should be 10% of 
the sample projected for the larger parent study. 
For this current pilot study, it will be conducted on 10% of these 
admissions, so we need 21 cases for this pilot study in each arm (case and 
control groups). 
3. Outcomes: 
The primary outcome of the study will be to compare the technical 
success defined as complete variceal obliteration and complications rate 
including bleeding, pulmonary embolism (PE), ulcers, fever, paravariceal 

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injection & rebleeding. Secondary endpoints will be amount of 
cyanoacrylate used & number of sessions. 
4. Methods:  
      Each patient will be subjected to : 
 Written informed consent will be obtained from each patient, 
including a discussion on the procedure. 
 Clinical assessment including history taking and physical examination 
 Routine laboratory investigations including complete blood picture 
and serum creatinine. 
 Liver function profile (serum bilirubin, AST, ALT , albumin and 
prothrombin time). 
 The severity of underlying disease will be assessed by the Child-
Turcotte-Pugh score (CTP) based on serum albumin, bilirubin, 
prothrombin time, the presence of ascites and encephalopathy. 
 All procedures will be performed under deep sedation or general 
anesthesia in the left lateral position. 
 Intravenous antibiotics will be administered to all patients prior to the 
endoscopic procedure to minimize the risk of secondary bacterial 
infection. Oral or intravenous antibiotics will be continued for at least 
3 days following variceal injection. 
 
 Endoscopic procedure and technique: 
 
 Standard diagnostic upper endoscopy will be performed in order to 
classify the varices according to the classification of Sarin and Kumar. 
Only high risk GOV II and IGV I varices (>10 mm) will be included. 
 EUS examination will be done in all patients with a Pentax linear 
Echoendoscope EG3870UTK (PENTAX medical, Tokyo, Japan) 
attached to a Hitachi Avius ultrasound system (Hitachi Medical 
Systems, Tokyo, Japan). All EUS examinations will be done by two 
endosonographers. The echoendoscope will be positioned in the 

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distal esophagus at the level of the cardia to visualize the gastric fundus 
and intramural varices. 
 EUS will be used to display the vascular anatomy, in particular the 
feeding vein. GVs will be classified endosonographically according to 
Boustière et al which considered size of GVs and gastric wall 
abnormalities (Boustière et al., 1993): 
1: Size of GVs:  
 Grade 0 (none) 
 Grade 1 (small or non-confluent varies < 5 mm) 
 Grade 2 (large or confluent varices ≥ 5 mm) 
2: Abnormalities of gastric wall: 
1. Grade 0 (none) 
2. Grade 1 (thickening and brilliance of the third hyperechogenic 
layer with or without fine internal anechogenic structures). 
3. Grade 2 (visible vessels in the third layer which deform the 
entire wall, with penetrating varices). 
 EUS-guided injection of CYA will be done at entrance of  of the 
varix or the perforator veins when identifiable using a mixture (1:1) 
of 2-octyl-cyanoacrylate & lipidol using 19G EUS-FNA needle in 
Group I, or DEI of CYA in Group II. 
 
 Follow‑up after endoscopy: 
After the procedure, patients will be observed for 2 hours in the 
recovery room before being discharged. Endoscopic examination and 
Doppler EUS will be repeated in all patients at 3, and 6 months post-
procedure (or sooner with recurrent bleeding) to confirm eradication. 
Hemostasis, early post treatment bleeding and late post treatment 
bleeding will be recorded according to Baveno VI concensus.  
GVs will be considered obliterated by direct endoscopy when not 
visible and/or hardened to catheter palpation. Obliteration by Doppler 
EUS will be considered by visualization of clot and absence of Doppler 

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flow within the gastric wall. Repeat injection will be performed in the 
absence of obliteration. Direct endoscopic and Doppler EUS 
examinations will be repeated again at 3, and 6 months after each 
injection. 
Ethical considerations: 
Study protocol will be submitted for approval by the medical ethics 
research committee, faculty of medicine, Mansoura University. 
Informed written consent will be obtained from each participant 
in the study after assuring confidentiality. 
Statistical analysis: 
The collected data will be coded, processed & analyzed using SPSS 
program for windows. The appropriate statistical tests will be used when 
needed. The level of significance will be considered at 5% (P ≤ 0.05). 
 
 

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High risk gastric varices (n=  ) 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
   Other reasons (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Follow up obliteration & side effects (n= ) 
Allocated to EUS guided injection (n=  ) 
 Received EUS guided injection  (n=  ) 
 Did not receive EUS guided injection (give 
reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Follow up obliteration & side effects (n= ) 
 
Allocated to direct endoscopic injection(n=  ) 
 Received direct endoscopic injection (n=  ) 
 Did not receive direct endoscopic injection 
(give reasons) (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
 
Allocation 
Analysis 
Follow-Up 
Randomized (n=  ) 
Enrollment 

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