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ENDOSCOPIC MANAGEMENT OF OESOPHAGEAL AND GASTRIC VARICES
SHIV K SARIN, SANJAY K SATAPATHY
Department of Gastroenterology, GB Pant Hospital, New Delhi 110 02, India.
OESOPHAGEAL VARICES
Gastro-oesophageal varices develop in 50% to 60% of cirrhotic patients and approximately 30% of them will experience an episode of variceal haemorrhage within 2 years of the diagnosis of the varices.[1,2] Up to third to half of the patients with advanced liver disease and large varices die after the first attack of variceal bleeding.[3] Many factors contribute to the high mortality: torrential bleeding from the varices causing blood loss and added hepatic ischaemia, compromised hepatic functions, coagulopathy, infection and the time taken to control the bleeding. Pharmacological therapy, endoscopic intervention, balloon tamponade, surgical shunting and more recently, radiological treatment have been part of the armamentarium used to stop variceal bleed and to prevent recurrence and subsequent complication. A multidisciplinary approach often depending on the patient' clinical presentation and the optimal availability of the expertise and the resources available decides the choice of treatment modalities. Endoscopic management of variceal bleeding has unquestionably become the main stay since its rapid evolution in the last two decades. The current article specifically addresses only those issues that are particularly germane to the endoscopic management of variceal haemorrhage.
Diagnosis of Varices
Endoscopy is the gold standard for the diagnosis of varices,[6] gastric varices may some time pose difficulty in identification. Adequate air insufflations to the distal oesophagus are a must for correctly estimating the variceal size. Although oesophageal varices are easy to detect, gastric varices may some time pose difficulty in identification. Linear array endoscopic ultrasound, contrast-enhanced computed tomography scan, magnetic resonance angiography, transabdominal ultrasound and examination have recently been added to the list of investigation that has been used to locate are varices. Angiography can also be used to identify varices. Angiography is usually performed when severe upper gastrointestinal bleeding precludes adequate diagnostic endoscopy.
Endoscopic Therapy
Endoscopic management of varices consist primarily of sclerotherapy (EST); endoscopic variceal ligation (EVL), and more recently endoscopic loop ligation (ELL). Endoscopic procedures, especially the first two, are widely available and have the relative ease of learning safe and the potential of instituting this therapy at the time of diagnosis (i.e., during diagnostic endoscopy). EST and EVL are highly effective in controlling oesophageal variceal bleeding. Gastric varices in continuity with oesophageal varices along the lesser curve may or at other loci do also respond well to endoscopic treatment.
Endoscopic Sclerotherapy
The goal of EST is to inject a sclerosant that subsequently results in variceal thrombosis and obliteration. The most frequently used sclerosants are sodium morrhuate, ethanolamine, sodium tetradecyl, and absolute alcohol.[8] A freehand technique is most commonly preferred. During an acute bleed, the injections are usually directed at the bleeding site and given intravariceally. Both paravariceal and intravariceal sclerotherapy are effective in elective situation.[9-10]
Varices are injected beginning at the gastro-oesophageal junction, then at higher levels up to 5 cm to 7 cm from the gastro-oesophageal junction. The immediate haemostatic effect is most likely due to sealing of the bleeding site by the sclerosant and oedema; thrombosis occurs later. A weekly injection protocol is favoured to achieve 'early kill' of the varices; but is often difficult due to ulceration. Post-sclerotherapy superficial ulceration on the varices are a necessary accompaniment of a successful EST. Superficial ulcers resulting from tissue necrosis are present in 90% of patients the day after EST and in 70% at one week.[11] However, deep ulcers, reaching the oesophageal wall are unacceptable and are associated with strictures and perforation. Most episodes of rebleeding occur before achieving variceal obliteration. After obliteration, varices tend to recur over time in 20% to 50% of individuals and require surveillance endoscopy, and if necessary repeat EST, every 6-12 months.[12-14]
Sclerotherapy is associated with a high incidence of local or systemic complications.[15-17] Retrosternal discomfort, pleurisy, pleural effusion, dysphagia, and fever have all been described. Encephalopathic patients should have endotracheal intubation during an acute bleed to protect the airway.[18] Severe complications in the form of bleeding from post-EST ulcers and oesophageal perforation may result in death in 15%.[19] The most significant long-term complication is stricture formation.
Endoscopic Variceal Ligation
The variceal endoscopic ligation developed from the concept of haemorrhoidal ligation by using a rubber band to strangulate a superficial blood vessel, resulting in vessel thrombosis; inflammation, necrosis, and sloughing of the mucosa and scar formation.[20,21] Initial studies used single banding devices which required use of an overtube, but subsequently, the availability of the multiband ligation devices have made the technique simpler and safer. The bands are deployed circumferentially in the distal oesophagus in a manner similar to that for EST. Five to 10 bands are typically deployed in a session. The banding device substantially reduces the viewing field because it is attached to the tip of the endoscope, rendering visualization difficult, especially in the setting of acute haemorrhage.
The ligation technique differs when approaching actively bleeding and non-bleeding varices with stigmata of recent haemorrhage. Once identified, the bleeding site whether spurting or non bleeding is directly ligated. If the bleeding site can't be ligated directly, a circumferential row of bands is placed distal to the suspected location of active bleeding. Endoscopic variceal ligation is as effective as sclerotherapy in stopping bleeding but is associated with less complication.[22-25] In contrast to chemical irritation from a sclerosant, the effect is local, and systemic complications are rare. While superficial mucosal ulcers are common, the development of dysphagia and strictures is rare.[11 ,26,27]
PRIMARY PREVENTION OF VARICEAL HAEMORRHAGE
Endoscopic Sclerotherapy
The improvement in survival in patients with portal hypertension, if at all possible, would be by preventing the first bleed. Several authors have studied the issue of prophylactic sclerotherapy for the prevention of 1st variceal haemorrhage.[28-40] A meaningful meta-analysis may not be possible out of these studies because of striking heterogeneity in the study population. However although majority of the study shows encouraging results in terms of reduction of bleed and bleed related mortality,[28-33,37,38] a few studies also shows harmful results.[34-35] The Veterans Affairs Cooperative study was the largest study that addressed these issues,[39] wherein 281 patients were randomized into EST or no treatment and was terminated prematurely due to unexplained excessive mortality in the treated groups, although there were significantly fewer episodes of oesophageal variceal bleeding (10 vs 19). PROVA study group did not find any significant difference in bleed, [40] when sclerotherapy was compared with betablocker or no treatment or betablocker plus EST, but found a higher mortality with BB plus EST group. In another study, 2 out of 43 patients were randomized to propranolol bleed compared to 9 out of 42 undergoing sclerotherapy and 13 of 41 controls.[41]
Sclerotherapy is therefore not recommended to prevent first variceal haemorrhage. The risk of sclerotherapy also needs to be weighed against the benefits, especially in relation to the primary prevention as these patients are at low risk for bleeding, as compared to those already bled.
Endoscopic Variceal Ligation for Primary Prevention of Variceal Haemorrhage
Since EVL has been shown to be safer alternative to EST in secondary prophylaxis, it became the logical choice for primary prophylaxis. EVL has been compared in 4 trials with no treatment. Results of these studies show a better outcome in terms of reduction of bleeding and bleed related mortality.[42,44,71] Since the time when these results were published, beta blockers were already established as the treatment of choice for primary prevention, strong evidence in favour of EVL as the modality of choice for primary prevention, strong evidence in favour of EVL as the modality of choice for preventing first variceal bleed could only come from a study comparing these modalities. The first such comparison was published by our group in 1999.[45] This and subsequent study observed the fact that EVL is superior as compared to BB or ISM.[46] A recent meta-analysis by Imperiale TF et al found,[47] among 601 patients in 5 homogeneous trials comparing prophylactic ligation with untreated controls, relative risks of first variceal bleed, bleed-related mortality, and all-cause mortality were 0.36 (0.26-0.50), 0.20 (0.11-0.39), and .55 (0.43-0.71), with respective NNTs of 4.1, 6.7, and 5.3. Among 283 subjects from 4 trials comparing ligation with beta-blocker therapy, the relative risk of first variceal bleed was 0.48 (0.24-0.96), with NNT of 13; however, there was no effect on either bleed-related mortality (relative risk (RR), 0.61; confidence interval (CI), 0.20-1.88) or all-cause mortality (RR, 0.95; CI, 0.56-1.62).[47] In conclusion, compared with untreated controls, prophylactic ligation reduces the risks of variceal bleeding and mortality. Compared with beta-blockers, ligation reduces the risk for first variceal bleed but has no effect on mortality. Prophylactic ligation should be considered for patients with large oesophageal varices who cannot tolerate beta-blockers. Subsequent research should further compare ligation and beta-blockers to determine the effect on mortality, and measure ligation's cost-effectiveness.
One recent trial with 172 patients found that,[48] EVL is no better than beta blocker in terms of preventing first bleed, but better than ISM. There were no statistically significant differences in terms of mortality between the treatment groups.
A series of studies have compared EVL to EST.[49-51] While in the most recent trials a variceal obliteration of greater than 90% has been seen in both techniques, the number of endoscopic sessions required to achieve this goal has been in favour of EVL. Despite the higher complication rate 22-60% (EST) vs. 2-35% (EVL), EST appears to have lower rate of variceal recurrence.
Since all these studies show either a better outcome or at least same as compared to alternative modality, it is tempting to recommend EVL in the primary prevention of variceal haemorrhage.
Management of Acute Variceal Bleed
Endoscopy in a patient with massive bleeding demands attention to details. Adequate volume and blood replacement before and during endoscopy is vital, so is protection of the airway in a patient that is liable to aspiration. This may be achieved with endotracheal intubation or the use of an over tube to protect the pharynx. Somatostatin or its analogues administered on admission, decreases the portal pressure and may temporarily staunch the bleeding. A twin channel endoscope allows easier suction of clots and the simultaneous irrigation and therapy. In patients with actively bleeding varices, one frequently encountered difficulty is the pooling of blood near the fundus and the cardia, obscuring the endoscopic view. One method that is useful is to patiently suck out as much of blood from the fundus as possible, and to site the patient up. Blood in the oesophagus and the cardia will gravitate down, giving the opportunity to identify the bleeding points and targeted therapy Occasionally turning the patient to one the right side may expose the fundus.
Endoscopic treatment is the most favoured approach for the control of active variceal bleed worldwide. Several randomized clinical trials have evaluated the effectiveness of EST. Endoscopic treatment has been compared to no therapy,[52] vasopressin or terlipressin,[53-57] somatostatin or octreotide,[58-61] and balloon tamponade.[54,62-65] A recent meta-analysis comparing emergency sclerotherapy with pharmacological treatment comprising 12 trials with 1146 patients couldn't found any convincing evidence to support the use of emergency sclerotherapy for variceal bleeding in cirrhosis as the first, single treatment when compared with vasoactive drugs.[66] As indicated previously, the main concern is the high incidence (18%) of severe complications-postsclerotherapy ulcer bleeding, perforation, and stenosis- and the high mortality rate of such complications (15%).[67] The high complication rates are in part responsible for the introduction of EVL. Endoscopic variceal ligation and EST as treatments of acute variceal haemorrhage have now been compared in a number of prospective studies. Either method achieves haemostasis in more than 80% of patients bleeding from oesophageal varices.[20,23,68-72] A recent meta-analysis comparing all the different modalities of treatment found that, ligation to be the most effective treatment (91.0%, 95% CI 82.4-96.3%); it was significantly more successful than vasoconstrictive treatment (vasopressin/terlipressin 68.7%, 61.7-75.2%; P < 0.002, chi-squared-test) or vasoactive treatment (somatostatin/octerotide, 75.9%, 68.1-82.6%; P < 0.02) treatment, but was not statistically better than sclerotherapy (81.1%, 71.7-88.4%).[73] The latter therapy was not statistically superior to medical treatment options. Calculations of estimated true effects, which take into account the weight of each study, rendered similar results.
Band ligation, besides not being superior to sclerotherapy, it has got its inherent technical problem of a reduced field of vision because of the banding device attached to the endoscope in EVL is particularly acute in an active bleeding episode and makes the procedure more difficult than EST.
Combination Therapy
Modalities with differing mechanisms of action may produce additive if not synergistic results. Eight studies[74-78] have compared endoscopic therapy (EST or EVL) and endoscopic therapy combined with vasoactive drugs (octreotide, somatostatin, terlipressin) and vasoactive drugs alone in various treatment arms. A recent metanalysis have compared, endoscopic treatment versus endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding.[79] Eight trials involving 939 patients were evaluated by standard meta-analysis methods. Initial haemostasis, 5-day haemostasis, 5-day mortality, and adverse events were analyzed. Combined treatment improved initial control of bleeding (relative risk (RR), 1.12%, 95% confidence interval (CI), 1.02-1.23), and 5-day haemostasis (RR, 1.28; 95% CI, 1.18-1.39). The difference in favour of combined treatment remained significant when trials that used drugs other than octreotide or that included a low proportion of alcoholic patients (< 40%) or high-risk cirrhotic patients (< 35%) were excluded. Mortality was not significantly decreased by combined therapy (RR, 0.73; 95% CI, 0.45-1.18). Severe adverse events were similar in both groups. In conclusion, in patients with acute variceal bleeding, pharmacologic agents improve the efficacy of endoscopic therapy to achieve initial control of bleeding and 5-day haemostasis, yet fail to affect mortality.
PREVENTION OF RECURRENT VARICEAL BLEED
Endoscopic Treatment
The first line of therapy for secondary prophylaxis is endoscopic management. In 8 trials involving more than 1100 patients, EST has been shown to decrease the risk re-bleeding (40 to 50% vs. 70%) and death (30%-60%, versus 50%-75%) compared with no treatment.[14,51, 80-85] It is not clear however, how much one can attribute this benefit to the effect of sclerotherapy per se or because of the control of active bleed.
The first published multicentre controlled trial comparing EVL with EST concluded that EVL is as efficacious as EST but resulted in fewer treatment related complications and better survival and needed lesser number of sessions to eradicate varices. The wide disparity between the two techniques with regard to complication and survival led several other RCTs comparing EST with EVL. These results further confirmed the earlier finding with earlier variceal eradication, less complication and less rebleeding than EST.
A recent meta-analysis of 13 trials comparing EVL and EST favoured EVL in preventing early rebleeding (pooled odds ratio, 0.46; 95% confidence interval, 0.46-0.6); mortality was equivalent (pooled odds ratio, 0.84%; 95% confidence interval, 0.62-1.15).[86] However the variceal recurrence rate following EVL is higher compared to EST.[12,25,50,86,87] This recurrence has been predicted by endosonography[8] and has been linked to large paravariceal varices.[96] This possibly occurs because EVL does not thrombose the feeding veins to the varices. Most studies have not specifically addressed long term follow-up with respect to recurrence of varices. We have addressed this issue in our study wherein we have demonstrated a significantly higher recurrence rate with EVL as compare to EST.[25] Significantly more patients developed PHG after EST than with EVL. Frequency of gastric varices however do not differ. Studies comparing EVL or EST with combination therapy - -EVL+EST or EST+EVL shows no persuasive evidence that combination is better than either treatment alone. In a recent meta-analysis,[89] no significant difference was seen in cessation of actively bleeding varices (OR = 1.01; 95% CI = 0.43-2.36), variceal rebleeding (OR = 1.12, CI = 0.69-1.81), and mortality (OR = 1.1, CI = 0.70-1.74) in patients with variceal ligation versus patients receiving the combination (0.70-1.74) in patients with variceal ligation versus patients receiving the combination treatment of ligation and sclerotherapy. Treatment sessions required to achieve complete variceal eradication were similar in the two treatment arms. A significantly higher incidence of oesophageal stricture was seen in combination therapy (p < 0.001).
The current recommendation for secondary prophylaxis thus favours strongly for EVL. Only limitation of this therapy is that it has got greater chance of recurrence and may be difficult to band smaller varices.
Combination Endoscopic and Pharmacologic Therapy
A combination of endoscopic therapy and 2-blockade could improve the results obtained by either alone. Results of clinical trials, however, did not show that combination is unequivocally superior than sclerotherapy alone.[20 ,90-97] Only two of these studies found the risk of rebleeding to be lower with combination therapy than that with 2-blockers alone.[99,102] Although a recent meta-analysis[86] using many of the same studies found the combined treatment to be significantly better than sclerotherapy alone (pooled odds ratio, 0.65%; 95% confidence interval, 0.46-0.92),[86] because of significant qualitative heterogeneity these results should be interpreted with caution. Further, mortality rates were comparable between the two treatment arms (pooled odds ratio, 0.81; 95% confidence interval, 0.50-1.2992).[86]
ENDOSCOPIC MANAGEMENT OF GASTRIC VARICES
One of the first descriptions of gastric varices (GV), and its association with portal hypertension was published in the German literature in 1913.[98] The prevalence of GV in patients with portal hypertension has been reported to vary from 2% to 70%.[99-104] It is worthwhile to note that GV are significantly more common in bleeders than in non-bleeders (27% vs. 4%), perhaps indicating that GV develop at a more advanced stage of portal hypertension.[105]
Earlier studies primarily depend upon contrast radiography, splenoportography, and percutaneous transhepatic portovenography for detecting GV. Today, upper GI endoscopy remains the mainstay of diagnosis of GV. Newer diagnostic tools such as endosonography,[5 ,106] MR angiography and multislice CT scanning are likely to improve in future our accuracy to diagnose GV. It would however remain to be seen whether the collaterals identified by these imaging modalities correlate with endoscopically detected GV in the stomach. Patients with GV could be asymptomatic and detected incidentally or could present with upper gastrointestinal tract bleeding or rarely with hepatic encephalopathy. In nearly 3/4th of the patients. GVs are detected during treatment of bleeding oesophageal varices or at routine UGI endoscopy being done in a patient with portal hypertension. Less than 1/4th of the patients present with GV bleeding. Bleeding should be considered to have arisen from GVs, if: i) an active bleed or ooze is seen from the GV, ii) a clot is seen over the varix, or iii) in the presence of distinct large GV and absence of oesophageal varices, no other source of bleeding is detectable.
Management of Gastric Variceal Bleed
Current protocols for bleeding GVs have been adopted from the treatment of bleeding oesophageal varices. Haemostatic methods that use standard therapy for oesophageal varices have not been found effective for GV. Most reports of endoscopic treatment of bleeding gastric varices are small series, case reports, or retrospective reviews.[105,107-110] Only a few studies have prospectively compared the effectiveness and safety of different treatment modalities. Hence, despite nearly two decades of active interest, the management of GV remains controversial and largely empirical.
Primary Prophylaxis
Should non-bleeding GV that accompany bleeding oesophageal varices or non-bleeding IGVs be prophylactically treated? This can only be answered if more data on the natural history of GV bleeding becomes available in relation to the location, size, presence of red signs and Child's status of the patient. There is little long-term data on the outcome of any treatment modality on survival in such patients. Thus, prophylactic treatment of GV is not warranted in general at the present time. However, as mentioned above, since patients in whom GOV 1 persist after obliteration of oesophageal varices bleed significantly more often, they form a group which requires prophylactic treatment.
It is known that fundal (GOV2 and IGV 1) varices are at a higher risk of bleeding than junctional varices (GOV 1).[105,107] Large fundal varices with red signs are even more likely to bleed.[111] Therefore, large fundal varices should constitute the subset which could be treated prophylactically. Kim et al.[111] in their prospective study documented a bleed rate of 53% from fundal varices > 2 cm in size in a median follow-up of 15.2 months. According to the available data, rebleed rate after glue injection or transjugular intrahepatic portosystemic shunt (TIPS) is < 30% over a similar follow-up period. Therefore, it seems logical to undertake clinical studies to assess the utility of prophylactically treating large fundal varices.
Acute GV Bleeding
The treatment goals are the same as for oesophageal varices: to control acute bleeding and to prevent rebleeding.
Indications of treatment
1. Active bleed from gastric varices.
2. Stigmata of recent bleed on gastric varices.
3. History of previous bleed and presence of gastric varices as the only source of bleed.
These patients need to be treated according to the type of GV and the expertise available. Sometimes however, it is not possible to determine whether a patient with oesophagogastric varices is bleeding from oesophageal or gastric varices. In such a situation, opinions differ on which varix should be injected first, oesophageal or gastric! An active bleed from GOV1 could be controlled by sclerotherapy, variceal ligation, or glue injection of oesophageal varices. For bleeding GOV2, there is however, no clear information. We recommend to ligate the oesophageal varices and inject the GOV2 with glue at the same session.
Secondary Prophylaxis
The end-point of treatment in patients who have bleed from GV should be eradication of varices as the rebleeding rate is significantly higher in those in whom eradication is achieved than in those in whom varices do not disappear.[109]
GASTRIC VARICEAL SCLEROTHERAPY
Gastric variceal slcerotherapy (GVS) could be done intravariceally or by a combination of intravariceal and paravariceal injections. Initial control of active bleeding has been reported with GVS in 40-100% cases.[112-119] Two studies have shown equal efficacy of emergency GVS for GOV1 and GOV2,[113,117] while studies by Oho et al. and Gimson et al. show higher success rate for GOV1 as compared to GOV2.[115,118] Chiu et al did emergency GVS in 27 patients with isolated gastric varices with a success rate of 67% and rebleed rate of 18% at 48 hours.[114]
The major problem with GVS is a high rebleed rate. This rebleeding could be due to rapid blood flow in GVs, making formation of a thrombus difficult. The early appearance of ulceration in incompletely obliterated varices predisposes to recurrent bleed which usually occurs after the first or second GVS session. Moreover, unlike oesophageal variceal ulcers, which are generally mucosal, ulcers following GVS are deep and submucosal. Approximately 50% of the post-GVS bleeds are from ulcers.[104,113,118] Chang et al have shown a higher rebleeding rate (70% vs. 30%) with sodium tetradecyl sulphate (STD) as compared to 50% glucose water and delayed ulcer healing (13± 5 vs. 6± 2 d).[114] Once rebleeding occurs, it is difficult to control with repeat GVS, the success rate being only 9-44%.[104,113,118]
Using repeated GVS, variceal eradication can be achieved in 17-81%, with a bleed rate of 16-70% (Table 3).[113,115,118,119] Variceal obliteration is achieved in a higher proportion of patients with GOV1 (94%) than in patients with GOV2 (70%) and IGV1 (41%). Rebleeding is seen in 5.5%, 19% and 53% patients respectively, in the three types of GVs, respectively.[118] The recurrence rate of gastric varices has been variably reported from 0-25%.[113,115,118,119]
If an agent which produces less mucosal ulceration and achieves complete and rapid obliteration of GV is developed, it will significantly reduce the early rebleed rate following GVS. Poly-N acetyl glucosamine, a polysaccharide polymer originating from marine microalgae, has been demonstrated to produce rapid and effective haemostasis by stimulating erythrocyte aggregation and variceal eradication by inducing an inflammatory reaction in a rabbit model.[120] Clinical studies are awaited with this agent.
TISSUE ADHESIVES
Two tissue adhesive agents, n-butyl-2-cyanoacrylate (Histoacryl) and isobutyl-2-cyanoacrylate (Bucrylate) have been used, although the latter agent has been withdrawn from the European market because of concerns about carcinogenicity. Native cyanoacrylate is a liquid with consistency similar to water and therefore lends itself to intravariceal injection. When added to a physiologic medium such as blood, the cyanoacrylate rapidly polymerizes, forming a hard substance. Thus, after injection into a varix, the cyanoacrylate plugs the lumen and results in rapid haemostasis. Several weeks after the injection (two weeks to three months), the mucosa overlying the injected area sloughs off and a glue cast is extruded into the stomach. Since ulceration over the varix appears quite late as compared to GVS, it does not hinder with repeat glue injections and also reduces the risk of ulcer bleeding. Tissue adhesives, therefore, come close to the requirements of a good sclerosing agent for gastric varices.
Cyanoacrylate injection has been shown to achieve haemostasis in more than 90% of patients with acute GV bleeding, with an early rebleeding rate of 0-28%.[105,109,116,117,121-127] Glue injection in 1-2 sessions can achieve variceal obliteration in 87-100% patients.[98,105,109,121,123-127] The term obliteration more accurately describes the desired immediate endpoint for glue injection of GV than eradication since a varix occluded with cyanoacrylate may remain endoscopically visible for many weeks. The methods used to assess the success of variceal obliteration include palpating the varix with a blunt instrument (soft versus hard), radiographic visualization of varices filled with lipiodol and cyanoacrylate mixture, and endoscopic ultrasound[105] (absence of hypoechoic vascular channels in fundus and cardia). The clinical significance of using endoscopic ultrasound to define eradication remains to be assessed in terms of low rebleeding rate and better survival.
Though the glue is injected like a sclerosant, its unique adhesive properties necessitate some modifications in the technique. It is important to ensure the intravariceal position of the needle. To prevent damage to the scope due to the adhesive, lipiodol, an oily contrast agent, or silicone oil, could be smeared at the tip of the scope and in the working channel. It is mixed with cyanoacrylate (in a ratio of 0.5 and 0.8 ml, respectively) to prevent premature solidification within or at the tip of the catheter during injection and to help in radiological evaluation of the injected material. Unnecessary suction should be avoided during the procedure.
The total amount of histoacryl injection per aliquot should not exceed 2 ml to decrease the risk of thrombotic complications.[128] Cerebral stroke, presumably due to anomalous right to left shunt in two cases,[129] fatal pulmonary embolization in one patient,[130] bacteraemia in a patient with portal vein embolization,[131] splenic infarction[132] and formation of retrogastric abscess[133] have been reported after injection of cyanoacrylate in patients with bleeding gastric varices.
These complications caution us to the indiscriminate use of glue in all patients with variceal bleeding. However, for patients with GV, the benefits of glue injection outweigh the potential risks. The concern about the potential carcinogenicity of cyanoacrylate observed in rats are probably ill-founded.[133] So far, there are no reports of carcinogenicity in over 2,000 patients treated for variceal bleeding with cyanoacrylate.
Comparison of Gastric Variceal Sclerotherapy and Glue Injection
Three studies have compared sclerotherapy using ethanolamine oleate (5%) or absolute alcohol and cyanoacrylate injection in acute gastric variceal bleeding.[116,117,134] Ogawa et al.[116] in their retrospective study reported a significantly higher haemostasis rate with cyanoacrylate compared with ethanolamine oleate (100% vs. 81%). While 6 of 17 (35%) patients rebleed at 2 weeks in the ethanolamine oleate group, none rebled in the histoacryl group. While 5 of 21 (23.8%) patients died in ethanolamine group, none died of bleed in the cyanoacrylate glue group. Oho et al.[117] in their prospective, nonrandomized study of 53 patients with acute GV bleed, reported histoacryl to be significantly more efficacious in achieving haemostasis than ethanolamine oleate (93% vs. 67%). Three patients in each group rebled at one month. Three other patients in the cyanoacrylate group rebled six months after treatment from the site of polymer elimination. A randomized controlled trial done in our centre in 35 patients with isolated gastric varices showed that cyanoacrylate is more effective in achieving initial haemostasis and in achieving faster variceal obliteration. The need for emergency surgical rescue was also much less in the glue injected group.[134]
The results of these three comparative studies indicate that cyanoacrylate is more effective than sclerosants like ethanolamine oleate or absolute alcohol. The difference in the haemostasis rates between sclerosants and the glue is due to different mechanisms of action. Ethanolamine or absolute alcohol induce haemostasis by formation of a thrombus. While this is often possible in oesophageal varices, it is difficult to achieve in GVs because of rapid blood flow. Cyanoacrylate on the other hand, induces venous thrombosis instantaneously by polymerization regardless of the blood flow.
Thrombin
Human and bovine thrombin have been safely used in oesophageal as well as gastric variceal sclerotherapy, without any report of distant thrombosis. Williams et al.[135] using bovine thrombin, reconstituted to 1000 u/ml intravariceally, achieved initial haemostasis and obliteration in all 11 cases with 2 injection sessions. Rebleeding was observed in only one patient over a median follow-up of 9 months. Similar results have been reported in another study.[136] The most important advantages of this approach is the absence of any mucosal damage and post-sclerotherapy ulceration that is characteristics of sclerosants and tissue adhesives. The widespread evaluation of this technique is limited by cost, lack of availability of the product, which is yet to be approved by the FDA.
Endoscopic Variceal Ligation
Endoscopic variceal band ligation (EVL) is an effective and safe method for the management of bleeding oesophageal varices. The development of multiband ligating devices has made EVL technically easier even with endoscope retroflexed in the stomach.
Gastric variceal ligation (GVL) has been evaluated for the treatment of bleeding gastric varices in a prospective uncontrolled study by Shiha et al (Fig. 10).[137] These workers were able to achieve haemostasis in 89%, with rebleeding in 18.5% of cases. Obliteration of GV could be achieved in all patients with a median of 3 sessions. Ulcers were seen at the ligation site in all the patients one week later. One study has compared histoacryl injection with GVL in 16 patients. Both the methods were found to be equally effective in achieving haemostasis with a similar rebleed rate.[138]
More randomized studies would be needed before variceal band ligation can be recommended as a safe and effective modality for the treatment of GV.
Endoscopic-snare ligation
The major concern with GVL is incomplete inclusion of large GV during ligation and subsequent bleeding.[139,140] Many workers have therefore used a snare for ligation of GVs which are more than one centimeter in size.
Yoshida et al.[141] used a detachable snare with an inner diameter of 4 cm to tighten around the varix base, grasping the periphery of varix with a forceps through the second channel of the double channel scope. High success rates (83% - 100%) in the control of acute GV bleed and variceal eradication with low recurrence rates have been reported by them and other workers (Table 7).[139-144] While no significant ulcer related complications were seen, gastric perforation was reported in two patients in one study.[139]
There are no human randomized controlled studies comparing various modalities for the treatment of gastric varices. Jutabha et al.[145] have compared sclerotherapy, cyanoacrylate injection and rubber band ligation in a randomized, non-blinded study in canine gastric varices. They reported that intravariceal sclerotherapy was the fastest and easiest to perform. Rubber band ligation was intermediate in technical ease, but it caused the largest and deepest ulcers and had the highest rate of stigmata of ulcer haemorrhage and secondary bleeding. Cyanoacrylate injection was the most cumbersome endoscopic method to perform. All the three treatments were effective for controlling gastric variceal bleeding.
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