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 Table of Contents  
REVIEW ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 3-11

Variceal bleeding: Current issues


Department of Medicine, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia

Date of Web Publication7-Mar-2014

Correspondence Address:
Ibrahim A Al Mofleh
Editorial Office, SJMMS, P.O. Box 1982, Dammam 31441, Kingdom of Saudi Arabia

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DOI: 10.4103/1658-631X.128397

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  Abstract 

Portal hypertension (PHT) is a serious sequel of liver cirrhosis. Eventually, varices develop, grow in size, and bleed. Several diagnostic modalities including transient elastography (TE), capsule endoscopy, CT scanning, and platelets count/spleen diameter ratio (PSR) have recently been introduced. Predictors of bleeding include large varices, red signs, severe liver disease, and hepatic venous pressure gradient (HVPG)12 mmHg. Oral nonselective (NSBB) are recommended for primary prophylaxis in patients with medium-to-large size esophageal varices (EV) that have not bled. Patients with acute variceal bleeding (AVB) should be resuscitated and managed in an intensive care unit. Vasoactive drugs should be started immediately aimed at a better control of bleeding and facilitation of a subsequent endoscopy. Terlipressin controls bleeding and mortality and is considered as the drug of choice. Antibiotic prophylaxis significantly improves survival compared with placebo. Early diagnostic and therapeutic endoscopy in patients with major bleeding enhances control of bleeding, reduces risks of rebleeding and mortality. The use of erythromycin prior to endoscopy clears the stomach, reduces the need for second endoscopy and blood transfusion, and shortens the length of hospital stay. Restricted transfusion strategy prevents portal pressure rise and improves the survival rate. The current recommendation is to treat AVB with a combination of vasoactive agent, EVL, and antibiotics. All patients who survive an episode of AVB should undergo secondary prophylaxis. Transjugular intrahepatic portosystemic shunt (TIPS) using covered stent represents the first-choice rescue treatment. Early TIPS insertion significantly reduces treatment failure, rebleeding, and mortality. Also, insertion of esophageal SX-Ella Danis stent in patients with refractory VB effectively controls bleeding. The data required for this review were obtained mainly through PubMed and Google search.

  Abstract in Arabic 

ملخص البحث :
تستعرض هذه المقالة ارتفاع الضغط ألبابي الناتج عن تليف أو تشمع الكبد والتي قد تؤدي إلى تكون الدوالي وخاصة في المرئ مسببة في بعض الأحيان إلى نزيف، قد يكون حادًا ومهددًا حياة المريض. توجد حاليا طرق عدة إلى تشخيص ارتفاع الضغط ألبابي، منها الأشعة المقطعية والتنظير وغيرها، كما توجد توقعات لاحتمال النزيف مثل حجم الدوالي واستفحال تليف الكبد. ينصح بتناول بعض الأدوية كوقاية أولية من احتمال نزيف الدوالي. أما في حالة النزيف فيحتاج المريض إلى رعاية خاصة في العناية المركزة بإعطاء الأدوية المساعدة على إيقاف النزيف، كما أن التنظير وحقن أو ربط الدوالي النازفة يلعب دورا مهما في إيقاف النزيف. ويستعرض الكاتب الخطوات الأخرى التي يجب إتباعها عندما يتخطى المريض هذه المرحلة.

Keywords: Bleeding, diagnosis, esophageal varices, portal hypertension, treatment


How to cite this article:
Al Mofleh IA. Variceal bleeding: Current issues. Saudi J Med Med Sci 2014;2:3-11

How to cite this URL:
Al Mofleh IA. Variceal bleeding: Current issues. Saudi J Med Med Sci [serial online] 2014 [cited 2017 Apr 24];2:3-11. Available from: http://www.sjmms.net/text.asp?2014/2/1/3/128397


  Introduction Top


The foremost cause of liver cirrhosis, portal hypertension (PHT), and development of esophageal varices (EV) is viral hepatitis and ethanol. PHT is progressive and EV formation increases gradually with time, grows in size, and bleeds. Bleeding from varices contributes to over 70% of all bleeding episodes in cirrhosis. Variceal bleeding is the most serious complication of PHT. It is associated with a high mortality rate mainly in the first 6 weeks after admission and is closely related to failure to control bleeding or to prevent early rebleeding. [1]

The rate of gastroesophageal varices is directly related to the severity of the liver disease and ranges from 40% to 85% in Child A and Child C, respectively. At the time of diagnosis, 30-40% of patients with compensated and 60-70% of those with decompensated cirrhosis have varices. [2],[3],[4] First bleeding episode occurs in 5-15% of patients in the first year and its risk is predisposed by the size of varices, the presence of red signs, and severity of liver disease. [5] Generally, 30% of patients with established diagnosis of EV are at risk to bleed within the first year of the diagnosis. [3] Approximately 70% of survivors develop recurrent bleeding within 1 year of the first bleed. [4] The 6 weeks mortality rate as a result of bleeding EV in cirrhotic patients is around 20%. [6],[7]

Diagnostic methods

Clinical assessment is the first step of diagnostic and prognostic evaluation of patients with PHT and EV. Nevertheless, endoscopic assessment and hepatic venous pressure gradient (HVPG) measurement are considered the gold standards in the diagnosis of EV in patients with cirrhosis and PHT. However, both methods are invasive and require expertise; therefore, several noninvasive diagnostic modalities including transient elastography (TE), platelets count/spleen diameter ratio (PSR), doppler-ultrasonography, capsule endoscopy, and CT scanning have recently been evaluated. Among the noninvasive techniques, TE has become a more popular method with findings comparable with HVPG in the detection of EV. [8],[9] However, Cammà et al. have found insulin resistance and PSR to be more accurate than TE in predicting the presence of EV in Child A cirrhosis. [10] A meta-analysis of 20 studies comprising over 3000 patients has shown that PSR is able to identify EV in cirrhosis with high accuracy and therefore its application may reduce the requirement for endoscopy among cirrhotic patients. [11]

Presently, other new modalities such as MR-elastography and acoustic radiation force imaging (ARFI) are under evaluation. ARFI-evaluated SS is capable to predict the existence of cirrhosis, but unable to identify the presence and the grade of EV as well as VB. [12] In contrast, multidetector CT-esophagography results have been comparable with those obtained by endoscopy. [13]

Another effective noninvasive device is the capsule endoscopy, which has been comparable to traditional endoscopy in the detection and evaluation of EV size with high sensitivity and specificity. However, these findings have not been consistent among different studies. [14] Although these noninvasive diagnostic modalities are promising, nonetheless more studies are required to confirm their efficacy in the diagnosisof EV. [9] Despite the current progress in diagnostic evaluation, none of these techniques substitute endoscopy and HVPG neither in the diagnosis nor in the prognostic evaluation of EV. [15]

To determine HVPG, measurement of wedge hepatic venous pressure (WHVP) is important. It is measured by a balloon catheter inflated in the hepatic vein until total occlusion. The pressure at the tip of the catheter is identical to the portal pressure. [16] Hepatic venous gradient is obtained by subtracting the free hepatic venous (FHVP) pressure from wedge hepatic venous pressure [HVPG = WHVP-FHVP]. [17],[18] HVPG 5 mmHg is considered abnormal and 10 mmHg is clinically significant and associated with increased risk of VB and other PHT-linked complications. [19] HVPG is considered as the gold-standard technique for diagnostic and prognostic PHT evaluation, while noninvasive methods are considered as complementary tests. [2],[20],[21],[22]

Prognosis

With time almost all cirrhotic patients will develop varices and 30% are expected to bleed within the first year with a high mortality rate complicating the first bleeding episode. The mortality rate (30-50%) is interrelated with liver disease severity. [3] Majority of mortality cases are encountered within the first 6 weeks following the bleeding episode with a rate of 20. [2] Approximately 60-80% of patients carry the risk of rebleeding within 1 year after the first bleeding episode and 30% estimated mortality rate. [2],[3]

Besides its diagnostic value, HVPG also offers an important prognostic value in the evaluation of patients with PHT. [9] Persuasively HVPG has been accepted as a prognostic predictor of VB. The risk of variceal rupture increases when HVPG exceeds 12 mmHg. [23],[24] Conversely, the drop of HVPG below 12 mmHg or 20% in response to pharmacological treatment is associated with a significant fall in the rates of first bleeding and rebleeding. [24] as well as other PHT-induced complications with improved survival. [16]

Nowadays HVPG measurement is debatable. A group of investigators have considered the evaluation of hemodynamic response to pharmacological treatment as the main indication for HVPG measurement. However, in respect of cost, requisite for proper equipment, and trusty operators, its use has to be restricted to specialized liver units. [18] Other group of investigators have conversely advocated the use of HVPG as the appropriate predictor of VB, other PHT-related complications, and survival. Hence, it has been considered as the only proper technique to assess the response to pharmacological therapy and herewith it provides decisive prognostic information. [25] Nevertheless, a number of strict criteria have to be considered for its interpretation. [24]

Predictors of severity

Predictors of portal hypertension and esophageal varices


The role of ARFI-evaluated SS in predicting EV, their size, and risk of bleeding has been debatable. While Bota et al. have reported a very good predictive ability to detect cirrhosis, nonetheless, it lacks ability to identify the existence and the size of EV as well as the risk of VB. [12] On the contrary, Takuma et al. have reported the usefulness of SS measurement in identifying cirrhosis, EV, and high-risk EV. Cutoff values of 3.18 and 3.30 m/s have identified patients with EV and those with high-risk EV with 75% and 72.1% accuracy rates, respectively. On the other hand, a cutoff 3.3 m/s has ruled out the presence of high-risk varices in patients with cirrhosis and hence, it could be used as an initial noninvasive screening test. [26] Similarly, Wang et al. have found TE to be useful in predicting EV and their size, thus it may determine patients who require endoscopic surveillance. [27] While PSR is able to identify clinically significant PHT and EV in patients with decompensated liver disease, combined data obtained from LS, spleen diameter, and platelet count can identify clinically significant PHT and EV in patients with compensated cirrhosis. [28]

Predictors of variceal bleeding

A variety of factors including severity of liver cirrhosis, enduring alcohol consumption, and high HVPG 12 mmHg are associated with an increased risk of bleeding. The risk of bleeding is also increased and linked with the presence of cherry red spots, wale signs, nipple, and the larger size of varices. [5],[29]

Predictors of hospital mortality

Both Child-Pugh score and Model for end-stage liver disease (MELD) are used to predict mortality; however, MELD has been superior to Child-Pugh score in predicting VB-related in-hospital mortality. [30] In addition, MELD score pinpoints patients with higher in-hospital mortality risk. [31]

Predictors of treatment failure and mortality

In patients with acute variceal bleeding (AVB) easily accessible clinical data have been identified that provide valuable information for determining the initial response to therapy and prognosis. HVPG measurement provides important prognostic information in patients with PHT. [10] In cirrhotic patients, MELD score and Child-Pugh score designate a residual liver function alteration and hence they may be utilized as a survival predictor. Furthermore, MELD score ascertains those with a higher intra-hospital mortality risk. [31] Both Child-Pugh score and MELD are used to evaluate liver function in patients with PHT. An analytical study of data on 212 cirrhotic patients with VB has compared these two modalities in predicting in-hospital mortality. While MELD has been superior in predicting VB-related in-hospital mortality, both modalities have been similar in predicting overall in-hospital mortality. [30]

Treatment of VB

Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis has been concluded by The Practice Guidelines Committee AASLD and The Practice Parameters Committee ACG [Table 1]. Treatment of variceal bleeding is initiated before, during bleeding, or after the first bleeding episode and accordingly classified into primary prophylaxis, AVB control, and secondary prophylaxis. [32]
Table 1: Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis

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1. Primary prophylaxis: Cirrhotic patients, who have not developed varices and those with small varices with the absence of endoscopic stigmata do not require treatment but they require a two yearly endoscopic surveillance. [33] This has also been supported by a large multicenter, placebo-controlled, double-blinded trial, which has not shown a benefit in the prevention of variceal development. [34] Therefore and due to adverse effects, nonselective β-blockers (NSBB) are not recommended for prevention of varices unless the small varices are associated with a high-risk of VB. [5],[35] Conversely, medium and large varices, which have not bled, require prophylactic treatment with oral NSBB. Beside their beneficial preventing effect of VB, they also decrease portal pressure and herewith PHT-related complications. [36],[37]

However, the use of NSBB may be limited due to intolerance or presence of concomitant cardiac or pulmonary disease. Approximately 15-20% of patients are unable to use NSBB. [32] Hence, in these patients variceal band ligation (VBL) represents the alternative modality for NSBB. A meta-analysis has demonstrated that VBL was better for primary prophylaxis of VB with less withdrawal rates due to adverse events. In another meta-analysis, discontinuation of NSBB has occurred in 53 patients compared with 7 patients on EVL with lack of difference in bleeding-related and overall mortality. Selection of modality depends on patient's tolerance, lower side effects, and patient's preference. [38],[39] Another meta-analysis of high-quality, randomized, controlled trials have shown a comparable efficiency of NSBB and EVL in patients with medium or large EV with comparable survival. [40] However, EVL is favored in patients with high risk medium or large varices, who have red wale marks or advanced liver cirrhosis. Combination of EVL and NSBB does neither alter the likelihood of first bleeding nor mortality. It rather increases the adverse events. [41],[42] On the other hand, a combination of EVL and propranolol has reduced the recurrence of varices. [41]

2. Acute variceal bleeding (AVB): Currently, there has been a significant decline in both hospitalization and mortality rates in patients with AVB in Europe and the USA. In the USA Jamal et al. have reported a drop of the hospitalization rate from 12.4 per 100,000 in the 1994-1996 period to 10.6 per 100,000 in the 2000-2002 period. [43]

Treatment of AVB has to be carried out in an intensive care unit and started with resuscitation and cautious hemodynamical stabilization. According to the recently updated Baveno V Guidelines (2010) patients have to be admitted to the ICU, receive vasoactive drugs, antibiotic prophylaxis, diagnostic and therapeutic endoscopy preceded by erythromycin [Table 2]. Terlipressin is the drug of choice and quinolons or IV cephaloprins are the favored antibiotics. Restricted transfusion strategy with hemoglobin targeted at 7-8 is associated with a higher survival rate. [7] All tasks should be performed as soon as possible after admission, preferably within 6-12 hours. [44] Combination therapy with vasoactive drugs (<30 min of hospitalization) and EVL (door to scope time <6 h) is accepted as first-line therapy. [45]
Table 2: ICU-Management of cirrhotic patients with AVB Guidelines recently updated at the Baveno V conference 2010

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Vasoactive agents

Vasoactive drugs are effective, considered as the first-line treatment, and they should be initiated as soon as possible after admission even in those with suspected AVB. Due to their efficacy and safety profile terlipressin, a synthetic analog of vasopressin and somatostatin are considered the first choice, while octreotide and vapreotide may be used as alternative agents. [46] Two meta-analyses have demonstrated terlipressin as the only vasoactive agent with effects on both hemostasis and mortality and thus it has been considered as the drug of choice. Administration of terlipressin has revealed a comparable effect to sclerotherapy in regard of hemostasis, rebleeding, and mortality. [47],[48] Terlipressin is given initially IV at a dose of 2 mg every 4 hours and can be titrated down to 1 mg IV every 4 hours once hemostasis has been achieved. Furthermore, additional meta-analysis has shown a statistically significant decline in all-cause mortality compared with a placebo. [49]

In randomized studies, both terlipressin and octreotide combined with EVL have been equally safe and effective in patients with AVB. [50],[51] However, Baik et al. have compared octreotide and terlipressin and reported a sustained hemodynamic effect of terlipressin on portal pressure and blood flow in patients with AVB. [52] Also in a meta-analysis, somatostatin has been shown to be superior to vasopressin and balloon tamponade (BT) with lack of virtual adverse events, but it lacks effects on mortality. [48]

Blood transfusion

Hemodynamic stabilization and maintaining the systolic blood pressure around 100 mmHg is important for prevention of renal failure and infection, which increase rebleeding and mortality risks. [53] On the other hand, excessive volume replacement may increase PHTN and rebleeding risk. [54] Cautious transfusion of packed red blood cells targeting a hemoglobin level of 7-8 g/dl as soon as possible after admission is advisable. [7] In patients with acute upper gastrointestinal bleeding, restrictive transfusion strategy has been associated with a higher 6 weeks probability of survival compared to liberal strategy. [55]

Antibiotic prophylaxis

Advanced cirrhosis and AVB promote infection. During hospitalization 20% of patients with VB are at a risk to develop infection. The risk rises further with the use of invasive procedures. Therefore, prophylaxis should be used in patients with advanced cirrhosis and AVB. [5],[56] A meta-analysis has shown survival improvement in patients who had antibiotic prophylaxis compared with the placebo group. Quinolones or IV cephalosporins are the ideal antibiotics. [48]

Spontaneous bacterial peritonitis, urinary tract infections, and pneumonia are the most frequent infections. They have been encountered in 50%, 25% and 25% of patients. [57] Two meta-analyses have revealed prevention of infection and significant improvement in short-term survival in AVB. [58],[59] A short-term prophylaxis 7 days with 400 mg twice daily oral norfloxacin or IV ciprofloxacin in case oral administration is not possible is the prophylaxis recommended by the American Association for Study of Liver Disease (AASLD) in any patient with cirrhosis and GI hemorrhage. In a randomized trial ceftriaxone has been superior to norfloxacin for bacterial infections prevention. In areas with a high prevalence of quinolone-resistant organisms, IV ceftriaxone (1 g/day) may be preferable. IV antibiotics can be replaced by oral norfloxacin as soon as oral intake is possible to complete the 7 day course. [5],[56]

Endoscopic therapy

Endoscopic therapy is the mainstay of treating AVB. Hemostasis may be achieved in 90% of patients. The two modalities endoscopic sclerotherapy and VBL are used; however, VBL is apparently more effective and safer and therefore it is the favored modality. In major AVB, early endoscopic therapy is associated with a better bleeding control and a decline in rebleeding risk and mortality. [48] In a meta-analysis constituting 23 trials comprising 1,860 patients the combination of NSBB with endoscopic therapy has been more effective than either therapies in reducing the overall and the variceal bleeding in cirrhosis. Nonetheless, combination therapy has not significantly affected mortality. [60] Additionally, two meta-analyses have shown a 5-day success rate of hemostasis of combined approach with VBL plus pharmacologic treatment compared to VBL alone. However, the combination treatment failed to demonstrate a reduction of mortality. [54],[61]

Value of erythromycin before endoscopy

Massive bleeding may obscure the endoscopic view, make diagnostic and therapeutic endoscopy difficult or impossible. Recent studies have demonstrated a beneficial effect of intravenous administration of erythromycin prior to endoscopy. In a randomized, double-blind, placebo-controlled study Altraif et al. have shown a significant improvement of endoscopic view and shortening of the index endoscopy duration. [62] Likewise, a recent meta-analysis has also demonstrated a significant gastric emptying, shorter hospital stay with a reduced requirement for a second endoscopy, and reduced amount of blood transfusion. [63]

Refractory AVB

Despite the progress in the treatment of AVB, 10-20% patients fail to respond to vasoactive and endoscopictherapy. They continue after a second endoscopic session to bleed or develop early rebleeding and require institution of rescue therapy. Patients with severe liver disease, persistent bleeding at endoscopy, and those who develop rebleeding are at highest risk to develop treatment failure. [64] Baveno V 2010 definitions and criteria for failure to control bleeding are displayed in [Table 3]. Failure to control variceal bleeding is complicated by a high mortality rate. They are salvaged by BT or transjugular intrahepatic portosystemic shunt (TIPS). Although these methods are useful to control bleeding, their use is limited by their complications.
Table 3: Baveno V (2010) definitions and criteria for failure to control bleeding

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TIPS in high risk treatment failure

The early insertion of TIPS within the first 72 hours of admission of patients with AVB and high risk of treatment failure has significantly minimized failure, rebleeding, and mortality rates. [64] The recent progress with the introduction of polytetrafluoroethylene (PTFE)-covered stents has enhanced patency and efficacy of TIPS. However, this technique has to be compared with other modalities used in PHT management. [65] A PTFE-coated stent has significantly reduced portal-caval pressure gradient at stent insertion and at 6- as well as at 12-month follow up. In addition, the use of covered stent has been associated with a significantly lower rate of dysfunction and fewer reinterventions. [66]

Self-expandable metal stents

Recently, a number of studies have evaluated the benefit of Self-Expandable Metal Stents (SEMS) in the treatment of refractory acute esophageal variceal bleeding (AEVB). [67] Insertion of SEMS has been easy in most patients, effective for the control of bleeding, and free of major complications. Therefore, in selected patients, SX-Ella DANIS stent can replace BT and TIPS and might be considered a substitute for BT. However, the number of patients has been small and prospective studies are warranted. [68] Other studies have also stated that fully covered SEMS was effective, can be kept in place for as long as 2 weeks, and used as a substitute for BT. [69] Further studies have also reported SEMS as an effective safe technique for the control of refractory AVB with a short mean duration of the procedure (10 ± 6) min. [70] Application of covered SEMS has been associated with lower rate of porto-systemic encephalopathy, significantly lower rates of shunt dysfunction, and clinical relapse compared to the non-covered stents. [71]

Surgery

Generally, as a result of the advances in drug treatment, therapeutic endoscopy, and TIPS, the requirement for surgical intervention has declined. However, a minority of patients, who may not respond to non-surgical rescue treatment and those, who may not comply to TIPS follow-up requirement, distal splenorenal shunt (DSRS) might be appropriate. [72] DSRS and TIPS have been evaluated in various trials and have had a similar in outcome with no significant differences in rebleeding, in rebleeding and survival, but TIPS patients require significantly more reintervention. [73],[74] In patients with recurrent VB and compensated liver disease, DSRS may be the favored. [75]

Candidates selected for surgical procedures should have preserved liver function and have no bleeding-related complications. [76] In these patients, the surgical approach has been associated with an excellent outcome with low morbidity and mortality rates. [77] Surgery-associated mortality rate in Child A has not significantly differed from mortality in patients with non-cirrhotic PHT. Hence, surgery can be suggested as a salvage procedure in patients with preserved liver function in whom non-surgical methods have failed. [78] Recently, the modified Sugiura technique has been considered as a life-saving and effective procedure for rescue therapy in AVB when alternative treatment fails, not indicated or not available. [79] Patients with severe liver disease are considered as the appropriate candidates for orthotopic liver transplantation. [76]

Emergency classical shunting procedures are associated with high mortality rate. Hence, the need for minimally invasive procedures is obvious. Zheng et al. have compared laparoscopic splenectomy and esophagogastric devascularization (LSED) with open splenectomy and esophagogastric devascularization (OSED), in patients with failure to control AVB. The duration of operation has been similar in both groups. However, LESD has been associated with less intraoperative blood loss and faster post-surgical gastrointestinal function normalization. None of the patients developed rebleeding or hypersplenism during the follow-up period and therefore, LSED as the minimally invasive procedure has been safe and accepted modality in uncontrolled AV. [80]

3. Secondary prophylaxis: Every patient with PHT who experienced the first bleeding episode should undergo secondary prophylaxis NSBB, VBL or combination. A large meta-analysis of 23 trials consisting of 1860 patients has demonstrated a significant reduction of the overall rebleeding rate compared with NSBB alone or VBL alone. [60] However, combination therapy has not influenced the mortality rate.This concurs with the current recommendations from the AASLD and ACG. [5] Garcia-Tsao. 2007.

Summary: Based on suspected VB, treatment is started at admission by resuscitation, administration of a vasoactive agent and antibiotics. In the presence of severe bleeding, rescue therapy is applied by EVL, self-expendable stent, or coated TIPS. EVL is performed in cases with mild or absent active bleeding. In all cases, vasoactive agents are continued for 3-5 days and antibiotics for a maximum of 7 days and followed by secondary prophylaxis with EVL+NSBB. Patients with decompensated cirrhosis and small varices should have more frequent subsequent screening. The use of erythromycin prior to endoscopy and cautious blood transfusion improve the outcome. Covered TIPS and self-expandable metal stents are promising salvage techniques.

 
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