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Thromboembolic Events Secondary to Endoscopic Cyanoacrylate Injection: Can We Foresee Any Red Flags?

1. Introduction

Variceal hemorrhage is a fatal presentation of portal hypertension, commonly seen in patients with decompensated cirrhosis. Current treatment protocol for gastroesophageal varices includes primary prophylaxis, management of acute bleeding, and secondary prophylaxis [1]. According to the Baveno VI consensus, a combination of nonselective beta blockers (NSBB) and endoscopic variceal ligation (EVL) for esophageal varices and cyanoacrylate injection for gastric varices are recommended as first-line therapy [2]. Compared to esophageal varices, gastric varices are lower in prevalence but are associated with a higher risk of hemorrhage and mortality [3]. The use of N-butyl-2-cyanoacrylate (NB2-CYA) for gastric variceal obliteration was first reported in 1986 and is currently well recognized as first-line therapy with a high hemostasis rate [4-6]. Large cohort studies have demonstrated the safety and efficacy of cyanoacrylate injection; however others have highlighted individual adverse events [7-9]. Occurrence of systemic embolization is often associated with patient morbidity and mortality. We hereby report a series of adverse events associated with cyanoacrylate injection for the treatment of gastric varices.

2. Methods

A retrospective case series study was conducted at a tertiary hospital. The hospital database was reviewed; approval was granted by the hospital's institutional review board (IRB). All patients who underwent endoscopic procedure had signed informed consent acknowledging the purpose and risk associated with the intervention. We included (1) patients with gastric varices with or without concurrent esophageal varices treated with injection of N-butyl-cyanoacrylate and (2) patients who experienced severe adverse events (SAE) associated with cyanoacrylate injection within 48 hours of the endoscopic procedure. SAE was defined as occurrence of death, life-threatening disability, or permanent deficit, resulting in a prolonged hospital stay.

All endoscopic procedures were commenced after an overnight fast. First, a routine endoscopy exam was performed to assess the extent of gastroesophageal varices that were classified according to Sarin's classification. Concurrent esophageal varices were graded according to the Japanese Society of Portal Hypertension [10]. Each patient received individualized therapy as deemed fit by the operator. Gastric varices were uniformly treated via the sandwich technique, which starts with an injection of lauromacrogol (Tianyu Pharmaceutical, Zhejiang, China), followed by Nbutyl cyanoacrylate (Beijing Suncon Medical Adhesive, Beijing, China), and then finished with flush of lauromacrogol [11]. The number of injection sites and volume of lauromacrogol and cyanoacrylate used directly correlated with the size of the varix. Multiple injection sites were chosen in attempt to obliterate the varix or varices in one session. Volume of lauromacrogol used ranged from 2 to 10 ml, while that of cyanoacrylate ranged from 0.5 to 2 ml, per injection site. Concurrent esophageal varices were treated with either endoscopic band ligation (EBL) or endoscopic sclerotherapy injection (EIS) determined by the operator.

Patients were hospitalized for postoperative observations for 24-48 hours. Any occurrence of severe adverse events (SAE), as previously defined, was recorded. Treatment and patient response secondary to the adverse events were documented. Patient follow-ups were accomplished via telephone interviews or out-patient services to determine survival or further complications.

A literature review of case reports on adverse events related to cyanoacrylate injection was also conducted, specifically, occurrence of embolic or infarction events. Detailed search strategy of Medline (R), from 1946 to present with daily updates, and Embase, from 1974 to March 20, 2017, is provided in the Appendix.

3. Results

A thorough review of the inpatient and endoscopy database was carried out from January 1, 2013, to December 31, 2016. A total of 652 patients who underwent N-butyl-cyanoacrylate (NBCA) injection as secondary prophylaxis for gastric variceal hemorrhage were identified. Based on the a priori established inclusion criteria, the detailed hospital record and treatment protocol of 5 patients were reviewed for the purpose of this study. Three of the five patients were male, ranging from 50 to 74 years. The cause of cirrhosis was PBC in the two female patients, while the remaining were due to HBV, HCV, or alcohol, respectively. Three patients were classified as Child-Pugh Class A, while the remainder were Child-Pugh Class B. Two of the five patients were admitted to our hospital due to an episode of acute variceal hemorrhage, while others had either achieved hemodynamic stability or were admitted for a follow-up endoscopic examination. Prior to the procedure, two patients (patients (4) and (5)) received a combination of hemostatic agents and somatostatin. None of the patients had concurrent HCC or hepatic encephalopathy. Detailed patient characteristics are summarized in Table 1.

Based on the findings of the routine endoscopy, one patient had IGV Type 1, one had GOV Type 1, while three had GOV Type 2 (Figure 1). All gastric varices were treated with the sandwich technique injection of lauromacrogol and cyanoacrylate. The total volume of cyanoacrylate used ranged from 1.0 to 3.5 ml (average 2.7 ml), without exceeding 1.5 ml per injection site. Patients with concurrent esophageal varices were treated with either endoscopic band ligation (EBL) or endoscopic injection sclerotherapy (EIS).

One female patient (patient (1)) suffered from cardiac arrest during the procedure. The bedside echocardiogram revealed an enlarged right ventricle and right atrium, widened vena cava, and shrunken left ventricle. Despite aggressive measures including drug and equipment resuscitation, the patient did not survive. Patient (2) experienced fever, severe abdominal pain, and rebound tenderness after the endoscopic procedure due to a large area splenic infarct (Figure 2), confirmed via CTA of the portal venous system. Two patients (patients (3) and (5)) became lethargic and confused and experienced loss of consciousness following endotherapy. Based on clinical symptoms and cerebral MRI findings, both were diagnosed with acute cerebral infarction (Figure 3). The last patient (patient (4)) experienced pain around the umbilical region with a low-grade fever (37.9[degrees]C) after the procedure. A subsequent abdominal CT and intestinal mesenteric CTA revealed intraluminal filling defects consistent with acute mesenteric ischemia (Figure 4). Detailed postoperative findings are listed in Table 2.

All patients received hemostatic medication after the endoscopic procedure as part of the standard protocol at our hospital to prevent postoperative hemorrhage (Table 2). Once the patient developed signs of systemic embolization, all hemostatic agents were suspended. All patients were treated with a subcutaneous injection of low-molecular weight heparin (LMWH). Three of the four patients responded well to therapy and were subsequently discharged. Follow-up interviews confirmed survival in all three patients. However, one patient (patient (4)) developed a recurrent GI bleed, presented as melena, after 5 days of anticoagulation treatment. The patient also developed hepatic encephalopathy and deteriorated rapidly. Extraordinary life sustaining measures were refused and the patient died 9 days after the initial procedure. The overall rebleeding rate was 20% and mortality rate was 40% in the five patients who experienced SAE after cyanoacrylate injection. Of the three patients who survived (60%), only 2 received follow-up endoscopy examination. Complete variceal obliteration was observed in one patient (50%), while the other patient had recurrent gastroesophageal varices (GOV Type 2) treated with consolidation EBL plus cyanoacrylate injection.

A retrospective review of the radiological studies was conducted in attempt to identify a potential explanation for the occurrence of an embolic event. Three of the 5 patients had evident spontaneous portosystemic shunts upon review of imaging studies, including one case of portorenal shunt (patient (3), cerebral infarction), one case of portoazygous shunt (patient (5), cerebral infarction), and one case of concurrent portorenal and portosystemic shunt (patient (1), pulmonary embolism). The remaining cases of mesenteric and splenic infarction had no prominent vascular anomaly.

In order to further identify similar reports of adverse events in present literature, a detailed search of Medline (R), from 1946 to present with daily updates, and Embase, from 1974 to March 20, 2017, was conducted (the Appendix). A total of 43 and 119 reports were retrieved from each database, respectively. Forty-two duplicates were removed and a thorough review of title and abstract of 120 articles was performed. Ninety-seven reports were further eliminated due to irrelevance and finally 24 articles, along with 4 case reports identified from other sources, were included for the purpose of this literature review.

Of the 27 studies included, majority of reported adverse events were pulmonary embolism, 12/27 (44.44%), and splenic infarction, 9/27 (33.33%), while others include cases of portal vein, renal vein embolism, sclerosant extravasation, myocardial infarction, diaphragmatic embolism, cerebral infarction, right atrium emboli, esophageal variceal embolism, and subsequent septicemia or DIC. Several adverse events were attributed to cardiac abnormalities such as patent foramen ovale, prompting right-to-left shunt. Other hypotheses include volume and speed of injection or intravariceal pressure, resulting in regurgitation through the portovenous system. Interestingly, many authors presumed the presence of spontaneous portovenous shunt, such as gastrosplenorenal shunt or anomalous arteriovenous shunts, as a culprit for distant embolization. However, none of the reports provided radiological or morphological evidence of the vasculature anomaly. The results of the literature review were summarized in Table 3.

4. Discussion

Gastric varices are associated with a high morbidity and mortality rate in patients with portal hypertension. The current recommendation for first-line treatment is endoscopic injection of tissue adhesives. Obliteration can be achieved in one session, but sometimes repeat sessions are required [39]. Although cyanoacrylate injection has proven to be safe and effective, several reports on related adverse events have also been documented [7]. Seewald et al. have emphasized the importance of a standardized technique, which can minimize the risk of embolization and local complications but also decrease variceal recurrence or rebleeding by effectively obliterating vessel tributaries. The recommended mixture proportion of N-butyl-2-cyanoacrylate to lipiodol is 0.5 ml: 0.8 ml, and injection of over 1 ml glue mixture may increase the risk of embolization [8, 40]. Researchers have also explored alternative treatments for gastric varices obliteration, minimizing or eliminating the use of tissue adhesives. Tan et al. conducted a randomized control trial comparing the efficacy of gastric variceal band ligation versus cyanoacrylate injection [41]. Meanwhile, Romero-Castro et al. reported fewer complications with endoscopic ultrasound-guided coil injection compared to that of traditional cyanoacrylate injection [42].

We report five cases of adverse events that occurred after the endoscopic injection of cyanoacrylate for the treatment of gastric varices. All cases involved the formation of systemic embolus, including cerebral vascular infarction, mesenteric infarction, splenic infarction, and pulmonary embolism. A retrospective review of radiological studies revealed presence of spontaneous portosystemic shunt (SPSS) in 3 patients with distant systemic emboli, including one case of portorenal shunt, one case of portoazygous shunt, and one case of concurrent portorenal and portosplenic shunt (Figure 5). Based on the clinical presentation and radiological findings, three cases can be ascertained as glue emboli, including the case of pulmonary embolism and two cases of cerebral infarction. The formation of spontaneous portosystemic shunts (SPSS) may serve as a shortcut for acute glue embolization, which calls into question the necessity of angiographic studies prior to endoscopic intervention and whether patients with diverging shunts should be tackled with a different therapeutic approach [43]. Our center has previously performed BRTO assisted cyanoacrylate injection for patients with large gastrorenal shunt or splenorenal shunt (data reported elsewhere). This procedure prevents the occurrence of systemic glue emboli for patients with evident portosystemic shunt; however, it is poorly tolerated by patients. BRTO assisted cyanoacrylate injection requires the patient to lay in a supine position with only local anesthesia and an angiography of the portosystemic system is performed via femoral access. After the portosystemic shunt is located a balloon is deployed and secured, while the endoscopist performs the subsequent cyanoacrylate injection.

The remaining cases of mesenteric infarction and splenic infarct remain controversial and cannot be ascertained as the presence of SPSS. A plausible explanation could be due to the injection of cyanoacrylate into the arterial system, which in some cases is located adjacent to the varix or is connected via an arteriovenous malformation. Glue emboli of the splenic artery may result in a large area splenic infarct as seen in patient (2). Another explanation is the regurgitation of tissue adhesives through the portovenous system, potentially due to high speed or volume injection or high intravariceal pressure. Patients with end-stage cirrhosis are also prone to clot formation, especially in the portal venous system [44]. The use of various hemostatic agents combined with a decrease in blood flow velocity, exacerbated by a stress event (endotherapy), may also be a probable explanation for an acute thrombus formation. Unlike other studies, our center employs lauromacrogol instead of lipiodol as a diluting agent for cyanoacrylate via sandwich technique [11]. Therefore, glue embolization is difficult to differentiate from a thrombus formation on imaging studies.

Antithrombotic treatment with LMWH is a fairly standard treatment protocol. However, in cases with recent interventional procedure or hemorrhagic episode, the use of LMWH can be precarious [45]. Development of a rebleed in such patients can be just as fatal as the adverse event itself. Anticoagulants are effective in the treatment of blood thrombus; however, the effect on glue emboli or improvement of patient outcome remains questionable.

The detailed literature review provided some further insights based on case reports of embolic events experienced after cyanoacrylate injection. Many authors theorized the presence of spontaneous portosystemic shunt as a probable explanation for embolization of tissue adhesives. However, no radiological or morphological evidence of vasculature malformation was provided. In our study, we meticulously reviewed the radiological imaging of all 5 patients and were able to identify the presence of spontaneous portosystemic shunt in 3/5 (60%) subjects.

Overall, the use of cyanoacrylate for gastric variceal obliteration is widely accepted with promising results. The safety of tissue adhesive injection is often guaranteed when endoscopist abides by the standardized sandwich technique [8, 40]. However, the necessity of preoperative imaging of the portovenous system should also be considered to identify patients with spontaneous portosystemic shunt (SPSS). In such cases, the risk of traditional endoscopic glue injection should be thoroughly vetted, or alternative treatment measures such as coil injection, TIPS, BRTO, or surgical therapy should be referred to. Utility of pre- and postoperative hemostatic agents should also be carefully considered to achieve a desirable hemostatic balance. Adverse events associated with tissue adhesives are often fatal and debilitating for patients; any red flags before endoscopic therapy should be well recognized by physicians, prompting well-rounded consideration to effectively avoid the occurrence of adverse events.

Appendix

Detailed Search Strategy

The search strategy used was Ovid Medline (R), from 1946 to present with daily updates, and Embase, from 1974 to March 20, 2017(see Table 4).

Ethical Approval

All procedures followed were in accordance with the ethical standards of the responsible committee of human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Consent

Informed consent was obtained from all patients for being included in the study.

Disclosure

The abstract of this manuscript has been presented at China 17th Congress of Gastroenterology, Xi'an, China, September 14-16, 2017. This article does not contain any studies with animal subjects.

https://doi.org/10.1155/2018/1940592

Conflicts of Interest

Yujen Tseng, Lili Ma, Tiancheng Luo, Xiaoqing Zeng, Yichao Wei, Ling Li, Pengju Xu, and Shiyao Chen declare that they have no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee of human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Authors' Contributions

Yujen Tseng and Lili Ma contributed equally to the manuscript and share first authorship.

Acknowledgments

This study was supported by the Innovation Fund of Shanghai Scientific Committee (no. 15411950501).

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Yujen Tseng (iD), (1) Lili Ma, (2) Tiancheng Luo, (1) Xiaoqing Zeng, (1) Yichao Wei, (1) Ling Li, (3) Pengju Xu (iD), (4) and Shiyao Chen (iD) (5)

(1) Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China

(2) Department of Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai, China

(3) Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China

(4) Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China

(5) Department of Gastroenterology, Endoscopy Center and Evidence-Based Medicine Center, Zhongshan Hospital, Fudan University, Shanghai, China

Correspondence should be addressed to Shiyao Chen; chen.shiyao@zs-hospital.sh.cn

Received 31 October 2017; Revised 20 January 2018; Accepted 31 January 2018; Published 3 April 2018

Academic Editor: Fernando G. Romeiro

Caption: FIGURE 1: Endoscopic findings of gastroesophageal varices (IGV Type 1 and F3/GOV Type 2) with red wale sign.

Caption: FIGURE 2: Large area splenic infarct based on CT angiography of the portal venous system.

Caption: FIGURE 3: Diffuse hyperdense signals ([left arrow]) on the cerebral MRI, indicative of acute cerebral infarction.

Caption: FIGURE 4: Intraluminal filling defect along the mesenteric vein and edema of the bowel wall ([left arrow]).

Caption: FIGURE 5: Spontaneous portosystemic shunt in the patient with IGV Type 1, presenting as portorenal and portosystemic shunt ([left arrow]). The coronal view shows gastric varices (*) connected to both the left renal and splenic vein through as large torturous, dilated venous shunt ([left arrow]).
TABLE 1: Summary of patient characteristics, preoperative management,
endoscopic findings, and subsequent treatment.

Patient     Cause of PH   Child-Pugh   Acute
                            Class      bleed

(1) 57y/F       PBC           A         No

(2) 74y/M     Alcohol         A         No

(3) 50y/M       HCV           A         No

(4) 51y/M       HBV           B         Yes

(5) 52y/F       PBC           B         Yes

Patient           Preoperative drug          Endoscopic
                                              findings

(1) 57y/F                None                 F0/IGV1

(2) 74y/M                None                 F2/GOV2

(3) 50y/M                None                 F3/GOV2

            Aminomethylbenzoic acid 0.4 g
                    Etamsylate 2 g
(4) 51y/M        Carbazochrome 80 mg          F3/GOV2
                  Hemocoagulase 1IU
                  Somatostatin 6 mg

                 Carbazochrome 80 mg
(5) 52y/F         Hemocoagulase 1 IU          F3/GOV2
                  Somatostatin 6 mg

Patient     Endoscopic     Volume of
            treatment    cyanoacrylate

(1) 57y/F      NBCA          3.5ml

(2) 74y/M   NBCA + EIS        3ml

(3) 50y/M   NBCA + EBL       3.5ml

(4) 51y/M   NBCA + EBL       2.5ml

(5) 52y/F   NBCA + EBL        1ml

TABLE 2: Postoperative events including subsequent severe adverse
event (SAE), patient outcome, and probable cause.

Patient     Postoperative          Adverse event
               drug use

(1)              None            Acute pulmonary
                                     embolism

(2)         Carbazochrome          Acute splenic
                80 mg               infarction
           Vitamin K110 mg
          Somatostatin 6 mg

(3)         Carbazochrome         Acute cerebral
                80 mg               infarction
          Somatostatin 3 mg
          Hemocoagulase 2 U

(4)       Hemocoagulase 1IU       Acute superior
          Somatostatin 6 mg    mesenteric infarction

(5)       Hemocoagulase 1 IU      Acute cerebral
          Somatostatin 6 mg         infarction

Patient       Treatment        Hospital stay

(1)              BCLS              1 day

(2)       Dalteparin 5000 IU      64 days
             Antibiotics
             (meropenem +
             vancomycin)

(3)       Dalteparin 5000 IU      13 days
              Edaravone
               Mannitol
            Dexamethasone

(4)         LMWH 4000 IU          9 days
           Simethicone p.o.

(5)          LMWH 4000 IU         42 days
              Citicoline
                 GM-1
            Dexamethasone

Patient   Outcome         Probable cause

(1)        Death        Large spontaneous
                         gastrorenal and
                        splenorenal shunt

(2)       Survival   Regurgitation of tissue
                       adhesive through the
                      portovenous system or
                           probable AVM

(3)       Survival    Spontaneous portorenal
                              shunt

(4)        Death     Regurgitation of tissue
                      adhesive through the
                      portovenous system or
                           probable AVM

(5)       Survival         Spontaneous
                        portoazygous shunt

TABLE 3: Summary of adverse events related to cyanoacrylate
injection found in current literature.

Study             Year    Country    Patient    Glue mixture
                                               (ratio), volume

Shim et al.       1996   S. Korea     59y/M     (0.5 : 0.8) 7
[12]                                              ml+ 2 ml

Battaglia et      2000     Italy      65y/F       (1:1)6 ml
al. [13]

Turler et al.     2001    Germany     18y/M    (1:1) 5 ml + 2
[14]                                                 ml

Tan et al. [15]   2002   Malaysia    53 y/M    (0.5:0.7) 6 ml
                                                    +1 ml

Cheng et al.      2004    Taiwan      65y/F      (1:1) 3 ml
[16]

Rickman et al.    2004      USA      55 y/M    (1:1) 4 ml + 2
[17]                                                 ml

Kok et al. [18]   2004   S. Africa    24y/F      (1:1)2 ml +
                                                 (1:2) 5 ml

Upadhyay et al.   2005     Oman      65 y/M       (1.5:2.1)
[19]

Alexander et      2006   Australia   52 y/M    (1:3) 4 ml + 2
al. [20]                                             ml

Liu et al. [21]   2006    Taiwan     42 y/M      (1:1) 2 ml

Martins Santos    2007    Brazil     53 y/M      (1:1) 1 ml
et al. [22]

Yu et al. [23]    2007    Taiwan     57 y/M    (1: 0.7) 1.7 ml

Chang et al.      2008    Taiwan      53y/M      (1:1) 2 ml
[24]

Marion-Audibert   2008    France      77 y      (1:1) 1.5 ml
et al. [25]

Abdullah et al.   2009   Malaysia     40y/M      (1:1) 3 ml
[26]

Park et al.       2010   S. Korea     34y/M          NA
[27]

Chen et al.       2011    Taiwan      57y/F     (1:1)4 ml + 6
[28]                                                 ml

Kazi et al.       2012   Australia    44y/F      (1:1) 4 ml
[29]

Miyakoda et al.   2012     Japan      76y/F    (1: 0.5) 1.5 ml
[30]                                           + (1: 0.5) 3.5
                                                     ml

Chan et al.       2012   Malaysia     44y/F     (0.5:0.8) 1.3
[31]                                                 ml

Singer et al.     2012      USA       75y/M       (1:1)3 ml
[32]

Mourin et al.     2012    France      69y/M          NA
[33]

Koksal et al.     2013    Turkey      33y/F      (1:1) 2 ml
[34]

Myung et al.      2013   S. Korea    55 y/F      (1:1) 2 ml
[35]

Nawrot et al.     2014    Poland      54y/F    (0.5:0.8) 12 ml
[36]

Chew et al.       2014      UK        34y/M      (1:1) 4 ml
[37]

Burke et al.      2017   Australia   25 y/F      1 ml + 3 ml
[38]

Study              Adverse event       Treatment

Shim et al.         Portal and            NA
[12]               splenic vein
                    thrombosis

Battaglia et          Int rap         Splenectomy
al. [13]            arenchym al
                    subcapsular
                  hematoma of the
                      spleen

Turler et al.        Pulmonary       Thrombectomy
[14]               embolism and     and ventilation
                    left renal         support;
                  vein; recurrent    operative and
                    left kidney        CT-guided
                    abscess (5         drainage
                      months)           (kidney
                                       abscess)

Tan et al. [15]    Pulmonary and      Supportive
                      splenic        treatment and
                    infarction        antibiotics

Cheng et al.        Sclerosant      Antibiotics and
[16]               extravasation      supportive
                                       treatment

Rickman et al.       Pulmonary      Oxygen support
[17]              emboli, splenic
                    infarction

Kok et al. [18]      Pulmonary       TIPS surgery
                  infarction and
                    septicemia

Upadhyay et al.    Inferior wall     Percutaneous
[19]                myocardial       occlusion of
                  infarction and    PFO followed by
                     cortical        TIPS surgery
                     blindness

Alexander et         Pulmonary       Prednisolone
al. [20]             embolism       and supportive
                                       treatment

Liu et al. [21]    Splenic vein     Antibiotics and
                    thrombosis        supportive
                                       treatment

Martins Santos        Splenic       Antibiotics and
et al. [22]         infarction        supportive
                                       treatment

Yu et al. [23]     Diaphragmatic      Supportive
                     embolism       treatment with
                                       narcotic
                                     analgesic and
                                    short course of
                                     terlipressin

Chang et al.      Pyogenic Portal     Antibiotics
[24]                  venous
                    thrombosis

Marion-Audibert      Pulmonary       BCLS protocol
et al. [25]          embolism

Abdullah et al.      Cerebral             NA
[26]                infarction

Park et al.        Right atrium           NA
[27]              emboli extended
                   from inferior
                     vena cava

Chen et al.         Esophageal       Cyanoacrylate
[28]                 variceal         hemostasis
                     embolism

Kazi et al.          Pulmonary           Blood
[29]                emboli and      transfusion to
                     pulmonary          correct
                     infarct,        coagulopathy
                   resulting in
                        DIC

Miyakoda et al.    Right atrium         Heparin
[30]                  emboli

Chan et al.           Splenic        Conservative
[31]                infarction         treatment
                                     (analgesics,
                                    antihistamine,
                                    and antiemetic)

Singer et al.        Pulmonary          Empiric
[32]                infarction      antibiotics and
                                    supportive care

Mourin et al.        Pulmonary       Anticoagulant
[33]                infarction        treatment +
                                     pneumonectomy

Koksal et al.         Splenic         Supportive
[34]                infarction         treatment

Myung et al.          Splenic             NA
[35]              infarction and
                     cerebral
                    infarction

Nawrot et al.        Pulmonary        Antibiotics
[36]               embolism with
                    septicemia

Chew et al.          Pulmonary        Intravenous
[37]                  emboli          diuretics,
                                        empiric
                                      antibiotics

Burke et al.         Pulmonary       BCLA protocol
[38]                  emboli

Study             Outcome       Probable cause

Shim et al.          NA          Large volume
[12]                              injection

Battaglia et      Survival      Resin occluded
al. [13]                         branches of
                                   splenic
                               vascularization
                                 or embolized
                               intrap arenchym
                                al vessels and
                                   had been
                                eliminated by
                                  macrophage
                                    action

Turler et al.     Survival       Spontaneous
[14]                             splenorenal
                                    shunt

Tan et al. [15]   Survival        Collateral
                                portosystemic
                               circulation and
                                  presumable
                                  anomalous
                                arteriovenous
                                  pulmonary
                                    shunts

Cheng et al.      Survival           High
[16]                            intravariceal
                                 pressure and
                               large volume or
                                high injection
                               speed of tissue
                                   adhesive

Rickman et al.    Survival            NA
[17]

Kok et al. [18]    Death          Collateral
                                vessels, size
                                 of varices,
                                  volume of
                                  injection,
                                 dilution of
                                   lipiodol

Upadhyay et al.   Survival      Patent foramen
[19]                                ovale

Alexander et      Survival       Large volume
al. [20]                          injection

Liu et al. [21]   Survival        Volume of
                                  injection

Martins Santos     Death        Arteriovenous
et al. [22]                         shunt
                                  (probable)

Yu et al. [23]    Survival       Portophrenic
                                    shunt
                                  (probable)

Chang et al.       Death            Direct
[24]                             injection or
                                regurgitation
                                  of tissue
                                adhesive along
                                  the short
                                 gastric vein
                                 and splenic
                                vein into the
                                 portal vein

Marion-Audibert    Death        Portosystemic
et al. [25]                    vascular shunt
                             (gastrosplenorenal
                                   shunt)
                               (reconstruction
                              with animal model)

Abdullah et al.   Survival   Patent foramen ovale
[26]

Park et al.       Survival    Gastrorenal shunt
[27]

Chen et al.       Survival            NA
[28]

Kazi et al.       Survival            NA
[29]

Miyakoda et al.    Death              NA
[30]

Chan et al.       Survival            NA
[31]

Singer et al.     Survival            NA
[32]

Mourin et al.      Death           Presumed
[33]                            portosystemic
                               vascular shunts

Koksal et al.     Survival        Retrograde
[34]                         embolization through
                               the splenic vein

Myung et al.      Survival   Patent foramen ovale
[35]

Nawrot et al.     Survival    Large spontaneous
[36]                          splenorenal shunt

Chew et al.       Survival            NA
[37]

Burke et al.       Death     Presumed collateral
[38]                             circulation

TABLE 4

Number                             Searches

(1)        (esophag* or esophag* gastr* or gastr* esophag* or gastr*
          oesophag* or gastroesophag* or gastrooesophag* or oesophag*
          or oesophag* gastr* or gastr*).mp. [mp = title, abstract,
         original title, name of substance word, subject heading word,
          keyword heading word, protocol supplementary concept word,
          rare disease supplementary concept word, unique identifier,
                                   synonyms]

(2)                       1 and (varic* or varix).mp.

(3)                         exp esophageal varices/

(4)                          exp gastric varices/

(5)                               (3) or (4)

(6)                               (2) or (5)

(7)      (cyanoacrylate or n-butyl-2-cyanoacrylate or NBCA or NB2CYA or
            NB2-CYA or tissue adhesive or tissue glue or glue).mp.
           [mp = title, abstract, original title, name of substance
           word,subject headingword, keyword heading word, protocol
            supplementary concept word, rare disease supplementary
                   concept word, unique identifer, synonyms]

(8)         (infarct* or embol* or advers* event* or severe advers*
           event* or complicat*).mp. [mp = title, abstract, original
         title, name of substance word, subject heading word, keyword
            heading word, protocol supplementary concept word, rare
            disease supplementary concept word, unique identifier,
                                   synonyms]

(9)                               (7) and (8)

(10)          (endoscop* therap* orendoscop* treat* or endoscop*
          inject*).mp. [mp = title, abstract, original title, name of
          substance word, subject heading word, keyword heading word,
               protocol supplementary concept word, rare disease
           supplementary concept word, unique identifier, synonyms]

(11)                             (9) and (10)

(12)       (case or case report* orcaseserie* or report*).mp. [mp =
           title, abstract, original title, name of substance word,
             subject heading word, keyword heading word, protocol
            supplementary concept word, rare disease supplementary
                  concept word, unique identifier, synonyms]

(13)                         (6) and (11) and (12)

Number   Medline results   Embase results   Search type

(1)          169513            268529        Advanced

(2)           14601            21427         Advanced

(3)           12569            17997         Advanced

(4)           12569             2864         Advanced

(5)           12569            19501         Advanced

(6)           14601            22623         Advanced

(7)           13485            26245         Advanced

(8)          1649685          3380532        Advanced

(9)           4356             10406         Advanced

(10)          8912             21219         Advanced

(11)           186              657          Advanced

(12)         4746115          6342357        Advanced

(13)           43               119          Advanced

Exp, explode.
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Title Annotation:Research Article
Author:Tseng, Yujen; Ma, Lili; Luo, Tiancheng; Zeng, Xiaoqing; Wei, Yichao; Li, Ling; Xu, Pengju; Chen, Shi
Publication:Canadian Journal of Gastroenterology and Hepatology
Article Type:Report
Date:Jan 1, 2018
Words:5886
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