Acute Variceal Hemorrhage

Acute Variceal Hemorrhage, descriptive class for MD medicine residents.

1. Acute Variceal Hemorrhage Pratap Sagar Tiwari 1 Total slides : 40

2. Target Audience: MD medicine residents Note: This slide is a compilation from various sources. All credit goes to original authors/researcher. Only for Academic purposes. [email protected] 2

3. Content Definition & Terms 1 Background 2 Anatomy of Varices 3 Management of VH 4

4. Definition: Acute variceal bleeding In a known or suspected case of PHT presence of hematemesis within last 48 h of presentation, and/or Ongoing melena, with last melanic stool within last 48 h. The acute variceal bleeding may be active or inactive at the time of presentation. Active bleeding is a state which is defined endoscopically, when spurting or oozing is seen from the varix 4 Varices are accepted as the bleeding source: when blood is seen arising from an EV—usually spurting; or actively oozing; or when there is presence of a sign of recent bleed on a varix (white nipple sign or overlying clot); or when there is presence of EVs with red signs (risk factors for bleed) and presence of blood in the stomach in the absence of another source of bleed; or when there is presence of EVs with red signs and clinical signs of upper GI bleed, without blood in the stomach. Sarin SK, et al. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int (2011) 5:607–624 Index bleed is defined as the first episode of bleeding with which the patient presents to the hospital. Recent bleed refers to a clinically significant bleed which occurred within 6 weeks of presentation. Past bleed refers to a clinically significant bleed which occurred more than 6 weeks of presentation.

5. Control of acute variceal bleeding refers to cessation of bleeding with hemodynamic stability for 24 h after therapy. In pts with active bleeding at endoscopy, cessation of bleeding should be confirmed at the end of the procedure. 5 Definition: Control of acute variceal bleeding Sarin SK, et al. Diagnosis and management of acute variceal bleeding: Asian Pacific Association for Study of the Liver recommendations. Hepatol Int (2011) 5:607–624

6. Definition: Failure to control AVH Failure to control AVH refers to failure of the combination therapy given and is defined by any of the following events, whichever occurs first, within 48 h from time combination (drugs ? EVL) therapy is instituted Development of fresh hematemesis after 2 h of combination (drugs ? EVL) therapy >2 g drop in Hb (6% drop in Hct ) if no transfusion is administered Continuous increase in HR and decrease of SBP with adequate infusion Death (note: the first three criteria would require modification of therapy) 6 3 g/dL drop in haemoglobin (9% drop of haematocrit ) within any 24 h period if no transfusion is given. UK guideline [1,2] Thabut D, Rudler M, Dib N, et al. Multicenter prospective validation of the Baveno IV and Baveno II/III criteria in cirrhosis patients with variceal bleeding. Hepatology 2015;61:1024–32. Ahn SY, Park SY, Tak WY, et al. Prospective validation of Baveno V definitions and criteria for failure to control bleeding in portal hypertension. Hepatology 2015;61:1033–40.

7. Background 7 GEV are one of the MC complications of LC. Approximately 50% of all patients with a new diagnosis of cirrhosis have gastrointestinal varices.[1] Their prevalence is 40% of Child A pts and increases up to 85% of Child C pts .[2]  Despite various efforts over the past decades, the 6 week mortality from EV bleeding still remains 20%.[ 3] VH is a severe complication of PHTN, causing 70% of all UGIB episodes in pts with LC.[4] In pts who do not have varices, new varices develop at the rate of approx 5-7% per year. An HVPG >10 mm Hg is the strongest predictor of the development of varices. Esophageal variceal bleeding is only a/with an HVPG of 12 mm Hg or greater. Once small varices develop, the rate of progression from small varices to large varices is again approx 10% per year.[5] ( 22% at one year and 51% at 3 years in pts with CP B/C, esp when alcoholic in origin). Mortality in pts who develop VH in addition to other decompensation : over 80% at 5-years ) . VH as an isolated decompensating event (20% at five-years). EASL Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database.  Gastrointest Endosc . 2007;65:82–88. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol 2007;102:2086–102. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006;44:217–31. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19:475–505. Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, Attili AF, Riggio O. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol. 2003;38:266–272.

8. Background 8 Annual risk of variceal bleeding among small and large varices is 5% and 15% respectively .[1] When pts bleed from EV, in approx 50% pts , the bleeding may stop spontaneously because hypovolemia results in reflex splanchnic vasoconstriction, which decreases PP . [2] Risk of rebleeding without endoscopic intervention is almost 60% with an increased mortality rate (33%).[3] With medical and endoscopic treatment , AVH is controlled in approx 80% to 90% of pts . The presence of active bleeding at endoscopy, HVPG >20 mm Hg, infection, advanced Child-Pugh class, and PVT complicating cirrhosis are a/with failure to control the initial bleed. Pts with early rebleeding, especially if they have a MELD score >18 and have required greater than 4 units of packed red cells for resuscitation, are at the highest risk of death. There is risk of rebleeding from EV within 6 weeks in up to one third of pts in whom variceal bleeding has been controlled, and almost one half of these pts will rebleed within 5 days of the initial bleed . North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med. 1988;319:983–989. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999;19:475–505. Bosch J, García- Pagán JC. Prevention of variceal rebleeding. Lancet. 2003;361:952–954. 

9. Gastro-esophageal Varices Flowchart reference: World J Gastrointest Pharmacol Ther . 2019 Jan 21; 10(1): 1–21. 9 EV are dilated veins located within esophageal wall and are usually supplied by the anterior branch of LGV . Clinically, GEV are classified by location into esophageal and gastric varices. Esophageal varices are often graded by size . A common system is as follows: F1 : small, straight varices. F2 : enlarged, tortuous varices, occupying less than 1/3 rd of lumen. F3 : large, coil-shaped varices, occupying more than 1/3 rd of lumen.

10. Gastro-esophageal Varices Flowchart reference: World J Gastrointest Pharmacol Ther . 2019 Jan 21; 10(1): 1–21. 10 EV are dilated veins located within esophageal wall and are usually supplied by the anterior branch of LGV . Clinically, GEV are classified by location into esophageal and gastric varices. Esophageal varices are often graded by size . A common system is as follows: F1 : small, straight varices. F2 : enlarged, tortuous varices, occupying less than 1/3 rd of lumen. F3 : large, coil-shaped varices, occupying more than 1/3 rd of lumen. Recent consensus from the AASLD includes a recommendation to simplify this using 2 grades (small and large) with a cut-off size of 5 mm. As a consequence, all the recommendations for large varices will apply also to medium varices for centres using the 3-grade classification.

11. ZONES of esophagus Venous drainage The gastric zone: which extends for 2 to 3 cm below the GEJ, comprises veins that are longitudinal and located in the lamina propria and submucosa . They come together at the upper end of cardia of the stomach and drain into SGV and LGV. 2. Palisade zone : this begins at the GEJ and extends cranially for 2–3 cm and is a direct extension of the veins of the gastric zone, which run in “palisades” or packs of longitudinally arrayed veins in the lamina propria. The perforating veins in the palisade zone do not communicate with extrinsic (periesophageal) veins so veins in this zones are most prone to bleeding and thus why when banding, oesophageal bands should be applied as close to the GOJ as possible.

12. Varices classification 12 B The Sarin classification is most commonly used for risk stratification and MX of GV. [1] GV are present in about 20% of pts with LC. GOV 1 are commonly managed following guidelines for EV.[2] Cardiofundal varices (GOV2 & IGV1) bleed less frequently. However, is often more severe, more difficult to control and shows a ↑ risk of rec bleeding and mortality (up to 45%) compared to EV.[1]  In CFV, the 5-year cumulative incidence of bleeding is 44% in the natural course, and the 1-year survival rate is 48% in case of bleeding. [3] Sarin SK, Lahoti D, Saxena SP, Murthy NS, Makwana UK. Prevalence, classification and natural history of gastric varices: a long-term followup study in 568 portal hypertension patients. Hepatology 1992;16:1343–1349. (also for table shown) De Franchis RBaveno VI faculty. Expanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752. T. Kim, H. Shijo , H. Kokawa et al., “Risk factors for hemorrhage from gastric fundal varices,” Hepatology, vol. 25, no. 2, pp. 307–312, 1997.  Pic src : Mehta, G., Abraldes , J. G., & Bosch, J. (2010). Developments and controversies in the management of oesophageal and gastric varices. Gut, 59(6), 701–705.

13. Anatomy of gastric varices 13 Gonzalez JM, et al. Management of fundic varices. Endoscopic aspects. Rev esp enfeRm Dig 2015. 107;8, pp. 501-508 Kim M, Lee K-Y. Understanding the pathophysiology of portosystemic shunt by simulation using an electric circuit. Biomed Res Int. 2016;2016(81):ID 2097363.7 Watanabe K, Kimura K, Matsutani S, Ohto M, Okuda K. Portal hemodynamics in patients with gastric varices: A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization. Gastroenterology. 1988;95:434–40. Chikamori F, Kuniyoshi N, Shibuya S, Takase Y. Correlation between endoscopic and angiographic findings in patients with esophageal and isolated gastric varices. Dig Surg. 2001;18:176–81. Kimura K, Ohto M, Matsutani S, Furuse J, Hoshino K, Okuda K. Relative frequencies of portosystemic pathways and renal shunt formation through the “posterior” gastric vein: Portographic study in 460 patients. Hepatology. 1990;12:725–8. Koito K, Namieno T, Nagakawa T, Morita K. Balloon-occluded retrograde transvenous obliteration for gastric varices with gastrorenal or gastrocaval collaterals. AJR Am J Roentgenol . 1996;167:1317–20. The afferent channel for gastric varix is mostly from LGV or posterior gastric veins. [1-3] The efferent channel for most GVs (80–85%) is the GRS , which opens into the LRV .[2,4] A B

14. Algorithm for the MX of AVH in pts with LC *Any of the following: varix spurting blood, varices with overlying clot or with white nipple sign, varices and no other lesion that would explain hemorrhage. **A short-term course (10 days) of PPI may reduce the size of post-banding ulcers. Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 14 /40 Restrictive transfusion strategy

15. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. 15 Background : The hb threshold for transfusion of red cells in pts with acute GIB is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. Outcome Measures and Definitions : The primary outcome measure was the rate of death from any cause within the first 45 days. Secondary outcomes included the rate of further bleeding and the rate of in-hospital complications . Methods : We enrolled 921 pts with severe acute UGIB and randomly assigned 461 of them to a restrictive strategy (transfusion when the hb fell below 7 g/dl) and 460 to a liberal strategy (transfusion when the hb fell below 9 g/ dl).

16. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. 16

17. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. 17

18. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. 18 Conclusions As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in pts with acute UGIB.

19. Blood transfusion strategy Kravetz D, Bosch J, Arderiu M, et al.: Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: influence of the extent of portal-systemic shunting. Hepatology. 1989; 9(6): 808–14. Kravetz D, Sikuler E, Groszmann RJ: Splanchnic and systemic hemodynamics in portal hypertensive rats during hemorrhage and blood volume restitution. Gastroenterology. 1986; 90(5 Pt 1): 1232–40. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. European Association for the Study of the Liver: EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69(2): 406–60. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65(1): 310–35. Reverter E, Tandon P, Augustin S, Turon F, Casu S, Bastiampillai R, Keough A, Llop E, González A, Seijo S, Berzigotti A, Ma M, Genescà J, Bosch J, García- Pagán JC, Abraldes JG. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology. 2014;146:412–419.e3. 19 Pts with LC have a hyperdynamic circulatory state . In a way, loss of intravascular volume through hemorrhage reduces PP , leading to cessation of active hemorrhage. Restitution of intravascular volume can induce a rebound ↑ in PP , which may lead to failure to control bleeding or re-bleeding or both. [1,2] In fact, in a landmark RCT[3], a “restrictive” transfusion strategy—Hb threshold for transfusion of 7 g/dL with a target range of 7 to 9 g/dL— was a/with a higher survival than a “liberal” strategy (Hb threshold for transfusion of 9 g/dL with a target range of 9 to 11 g/dL). Therefore, current guidelines recommend initiating transfusions when Hb levels decrease to <7 g/dL , and the target level is 7 to 9 g/dl.[4,5]

20. Blood transfusion strategy Kravetz D, Bosch J, Arderiu M, et al.: Hemodynamic effects of blood volume restitution following a hemorrhage in rats with portal hypertension due to cirrhosis of the liver: influence of the extent of portal-systemic shunting. Hepatology. 1989; 9(6): 808–14. Kravetz D, Sikuler E, Groszmann RJ: Splanchnic and systemic hemodynamics in portal hypertensive rats during hemorrhage and blood volume restitution. Gastroenterology. 1986; 90(5 Pt 1): 1232–40. Villanueva C, Colomo A, Bosch A, et al.: Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013; 368(1): 11–21. European Association for the Study of the Liver: EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69(2): 406–60. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65(1): 310–35. Reverter E, Tandon P, Augustin S, Turon F, Casu S, Bastiampillai R, Keough A, Llop E, González A, Seijo S, Berzigotti A, Ma M, Genescà J, Bosch J, García- Pagán JC, Abraldes JG. A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology. 2014;146:412–419.e3. 20 Pts with LC have a hyperdynamic circulatory state . In a way, loss of intravascular volume through hemorrhage reduces PP , leading to cessation of active hemorrhage. Restitution of intravascular volume can induce a rebound ↑ in PP , which may lead to failure to control bleeding or re-bleeding or both. [1,2] In fact, in a landmark RCT[3], a “restrictive” transfusion strategy—Hb threshold for transfusion of 7 g/dL with a target range of 7 to 9 g/dL— was a/with a higher survival than a “liberal” strategy (Hb threshold for transfusion of 9 g/dL with a target range of 9 to 11 g/dL). Recommendations regarding MX of coagulopathy and thrombocytopenia cannot be made on the basis of currently available data. PT/INR is not a reliable indicator of the coagulation status in pts with LC. However, platelet and plasma transfusion can be done in select patients who are hemodynamically unstable with active variceal bleeding (goal: platelet count > 50000/ μL and INR < 1.5)[6] Therefore, current guidelines recommend initiating transfusions when Hb levels decrease to <7 g/dL , and the target level is 7 to 9 g/dl.[4,5]

21. Algorithm for the MX of AVH in pts with LC *Any of the following: varix spurting blood, varices with overlying clot or with white nipple sign, varices and no other lesion that would explain hemorrhage. **A short-term course (10 days) of PPI may reduce the size of post-banding ulcers. Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 21 /40 Pharmacological treatment options

22. Pharmacological treatment options 22 Decrease PP by reducing portal flow secondary to splanchnic vasoconstriction. Decreases glucagon which has vasodilator properties. Also, recent studies suggest that octreotide has a local vasoconstrictive effect .

23. References are at the end of the slides 23 Somatostatin * Octreotide † Vapreotide ‡ Dose and duration 250 μg IV bolus then 250 μg/h infusion × 24 h to 168 h 50 μg IV bolus then 50 μg/h infusion × 24 h to 120 h 50 μg IV bolus then 50 μg/h × 120 h Efficacy, % Initial hemostasis 60 to 92 84 to 95 69 Rebleeding 15 19 (0.46, 0.32 to 0.67) § 16 at 42 days Mortality 9-38 at 42 days (1.16, 0.67 to 2.01) § 31 at 60 days (0.81, 0.48 to 1.35) § 14 at 42 days Complications Total, % 6.5 26 6 Severe Virtually none compared with placebo Pneumonia, Cardiac arrythmia, Paralytic ileus, Pulmonary edema No difference in major AE compared with placebo Moderate/mild Abdominal pain. Diarrhea, Hot flushes Abd cramps, pain, Nausea, Headache, Encephalopathy Hyperglycemia Comments Conflicting RCTs, No sig difference compared with placebo on MA All trials included endoscopic RX initially or after 48 h All pts received endoscopic RX in 12 h * 1-3, 4 ; † 4 ,5,6; and ‡ 7 . § RR versus placebo, 95% CI; The advantage of somatostatin and analogues is that they are safe and can be used continuously for 5 days or even longer.

24. References are at the end of the slides 24 Vasopressin * Terlipressin † Dose and duration 0.4 U IV bolus then 0.2 U/min to 1.0 U/min × 72 h initial dose of 2 mg IV q 4 hours and can be titrated down to 1 mg IV q 4 hours once hemorrhage is controlled Efficacy, % Initial hemostasis 0 to 80 81 (0.66, 0.53 to 0.82) ‡ Rebleeding 4.8 14 (0.99, 0.60 to 1.61) ‡ Mortality 36 25 at 42 days (0.66, 0.49 to 0.88) ‡ Complications Total, % 46 20 Severe Death (3%), Cardiac ischemia/arrhythmia, Mesenteric ischemia, Limb ischemia, Stroke, Bronchial constriction Limb ischemia, Hyponatremia, Seizure, Cardiac ischemia/arrhythmia, CCF, HTN Moderate/mild Headache, Abdominal pain, Nausea/vomiting, Tremor, Urticaria, Diaphoresis Atrial fibrillation, Abdominal pain, Skin lymphangitis, Nausea, Fever Comments Significant side effects because monotherapy limits its use Combination with nitroglycerin attenuates side effects but has not been shown to improve control of bleeding or mortality Only pharmacological agent shown to reduce mortality compared with placebo (RRR 34%) * 1,2-4 and † 5,6; ‡ RR versus placebo, 95% CI; Note; The reduction in splanchnic blood flow ↓ PP by approx 20%, even with a single dose of terlipressin . The PP drops between 15 and 30 minutes following administration, and the reduction lasts for approx 4 hours.

25. Terlipressin Moller S, Hansen EF, Becker U, Brinch K, Henriksen JH, Bendtsen F. Central and systemic hemodynamic effects of terlipressin in portal hypertensive patients. Liver 2000;20:51-59. Narahara Y, Kanazawa H, Taki Y, Kimura Y, Atsukawa M, Katakura T, et al. Effects of Terlipressin on systemic, hepatic and renal hemodynamics in patients with cirrhosis. J Gastroenterol Hepatol 2009;24: 1791-1797. Krag A, Hobolth L, Møller S, Bendtsen F. Hyponatraemia during terlipressin therapy. Gut 2010;59:417-418. 25 Terlipressin has affinity for both V1 and V2 receptors. Terlipressin selectively causes splanchnic and extrarenal vasoconstriction by stimulation of V1 receptors, which are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region and thereby reduces splanchnic blood flow and portal pressure .[1] Following Terli administration for 30 min there is an ↑ in MAP and SVR while the HR, CO, HVPG, and portal venous blood flow decrease.[2] Reduction in PP results in amelioration in the hyperdynamic circulation, thereby improving the effective circulatory volume and renal perfusion pressure. V2 receptor stimulation by Terli ↑ water reabsorption in the renal collecting ducts by increasing the number of aquaporin-2 water channels in the apical plasma membrane.[1,3] Hyponatremia may result in some pts.

26. Literature review 26 Akanksha Mathur ; Meta-analysis of 6 RCT (n=1129 ): The comparison of Terli and Octreotide showed them to be equally effective and safe therapeutic agents in pts of AVH. [1] AKANKSHA MATHUR, and ACHAL SHARMA. “A META-ANALYSIS COMPARING THE EFFICACY AND SAFETY OF TERLIPRESSIN AND OCTREOTIDE IN THE MANAGEMENT OF ACUTE VARICEAL BLEEDING”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 12, no. 12, Oct. 2019, pp. 73-76 Gøtzsche PC, Hróbjartsson A. Somatostatin analogues for acute bleeding oesophageal varices. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000193. Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database Syst Rev. 2003:CD002147. Wang C, Han J, Xiao L, Jin CE, Li DJ, Yang Z. Efficacy of vasopressin/ terlipressin and somatostatin/octreotide for the prevention of early variceal rebleeding after the initial control of bleeding: a systematic review and meta-analysis. Hepatol Int. 2015;9:120–129. Gøtzsche PC, et al analyzed 21 RCT (n= 2588 ) in aggregate and compared Somatostatin analogues to placebo or no treatment for variceal bleeding. The review found adding somatostatin to routine care did not reduce all-cause mortality or the risk of rebleeding , but reduced the average units of blood transfused by 0.7 units [2] Terlipressin was analyzed in a MA involving 1609 pts from 22 studies. Among those 22 studies, seven studies (443 pts) compared the effect of terlipressin to a placebo group . Terlipressin group was noted to have a statistically significant reduction in all-cause mortality (RR = 0.66, 95%CI: 0.49-0.88). Remaining studies compared terlipressin to somatostatin, octreotide, vasopressin or balloon tamponade. There was no significant difference in mortality or AEs between the groups[3,4].

27. Drug of choice in AVH 27 AASLD : Vasoactive drugs (somatostatin or its analogue, octreotide; vasopressin or its analogue, terlipressin ) should be initiated as soon as VH is suspected. UK : In all pts, vasoconstrictors such as terlipressin or somatostatin are recommended and should be started as soon variceal bleeding is suspected and continued until hemostasis is achieved or for up to 5 days. Octreotide is suggested if Terlipressin or somatostatin are unavailable . EASL : Either Terlipressin, somatostatin or octreotide are accepted drugs with proven efficacy. AGA: NO CLEAR APASL: TERLI FIRST CHOICE

28. Short-term prophylactic antibiotics de Franchis R, Baveno VI Faculty: Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015; 63(3): 743–52. European Association for the Study of the Liver: EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018; 69(2): 406–60. Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65(1): 310–35. Bernard B, Cadranel JF, Valla D, et al.: Prognostic significance of bacterial infection in bleeding cirrhotic patients: a prospective study. Gastroenterology. 1995; 108(6): 1828–34. Goulis J, Armonis A, Patch D, et al.: Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology. 1998; 27(5): 1207–12. Hou MC, Lin HC, Liu TT, et al.: Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004; 39(3): 746–53. Pauwels A, Mostefa -Kara N, Debenes B, et al.: Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection. Hepatology. 1996; 24(4): 802–6. Tandon P, Abraldes JG, Keough A, et al.: Risk of Bacterial Infection in Patients With Cirrhosis and Acute Variceal Hemorrhage, Based on Child-Pugh Class, and Effects of Antibiotics. Clin Gastroenterol Hepatol. 2015; 13(6): 1189–1196.e2. 28 Bacterial infections are reported in >50% of pts with LC and GIB and are a/with failure to control bleeding, high risk of re-bleeding, and increased mortality .[4-7] Therefore, timely short-term antibiotic prophylaxis is an essential step in the MX of these pts. [2,3] The importance of prophylaxis is incontrovertible in pts with advanced cirrhosis, whereas in pts with less severe disease, conflicting data have been published. In a retrospective study, Child A pts had a low rate of bacterial infection (2%) in the absence of antibiotic prophylaxis, and there was no difference in mortality between pts on and off antibiotics . In contrast, antibiotics were a/with a marked mortality reduction in Child C pts.[8] However, more prospective studies are needed to assess whether antibiotic prophylaxis can be avoided in Child A pts.[1]

29. Short-term prophylactic antibiotics Garcia-Tsao G, Abraldes JG, Berzigotti A, et al.: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017; 65(1): 310–35. 29 IV ceftriaxone (1 g/24 hours) for a maximum of 7 days is the first choice in pts with advanced cirrhosis, in pts receiving quinolone prophylaxis, and in hospitals where there is a high frequency of quinolone-resistant bacteria strains. Norfloxacin 400 mg twice a day may be used in the other pts and is rationally sound since it achieves selective intestinal decontamination. Local microbial epidemiology and resistance patterns may optimize the choice of antibiotic prophylaxis in specific centers. Prophylactic antibiotics should be used for a maximum of 7 days (consider discontinuing when hemorrhage has resolved and vasoactive drugs discontinued)[1] and their use should not be extended after discharge from the hospital.

30. EVL-induced ulcer bleeding 30 The prevalence of EVL-induced ulcer bleeding is reported to be upto 15 %. [1-4] Mortality is reported upto 40 %. [6] On the day after EVL, thrombi begin to develop in the strangulated vessels. Approx 3 to 7 days after the banding, the rubber band slip off and esophageal ulcerations develop, which heal within 2 to 3 weeks.[5] When early slippage of rubber bands occurs , before the occlusion of the varix with a mature thrombus, rebleeding from the ulceration may occur. Schmitz RJ, Sharma P, Badr AS, et al. Incidence and management of esophageal stricture formation, ulcer bleeding, perforation, and massive hematoma formation from sclerotherapy versus band ligation. Am J Gastroenterol 2001;96:437–41. Petrasch F, Grothaus J, Mossner J, et al. Differences in bleeding behavior after endoscopic band ligation: a retrospective analysis. BMC Gastroenterol 2010;10:5. Bambha K, Kim WR, Pedersen R, et al. Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut 2008;57:814–20. D’Amico G, De Franchis R, Cooperative Study G. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 2003;38:599–612. Nijhawan S, Rai RR, Nepalia S, et al. Natural history of postligation ulcers. Am J Gastroenterol 1994;89:2281–2. Vanbiervliet G, Giudicelli-Bornard S, Piche T, et al. Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study. Aliment Pharmacol Ther 2010;32:225–32.

31. Proton pump inhibitors 31 IV PPIs should be initiated in case of upper GI hemorrhage because peptic ulcers are the cause of bleeding in one third of the cases.[1] However, when portal hypertensive bleeding is confirmed , PPIs should be discontinued. Limited evidence suggests that short-term use (10 days) of PPIs might reduce banding ulcer size[ 2] without having a significant effect on bleeding. Because PPIs are a/with an ↑ risk of HE[3] , especially in those with recent bacterial infections[4] and with a high risk of 30-day re-admission [5], their use (if at all) should not be extended past the hospitalization period. Hsu YC, Lin JT, Chen TT, et al.: Long-term risk of recurrent peptic ulcer bleeding in patients with liver cirrhosis: a 10-year nationwide cohort study. Hepatology. 2012; 56(2): 698–705. Shaheen NJ, Stuart E, Schmitz SM, et al.: Pantoprazole reduces the size of postbanding ulcers after variceal band ligation: a randomized, controlled trial. Hepatology. 2005; 41(3): 588–94. Dam G, Vilstrup H, Watson H, et al.: Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology. 2016; 64(4): 1265–72. O'Leary JG, Reddy KR, Wong F, et al.: Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis. Clin Gastroenterol Hepatol. 2015; 13(4): 753–9.e1-2. Bajaj JS, Acharya C, Fagan A, et al.: Proton Pump Inhibitor Initiation and Withdrawal affects Gut Microbiota and Readmission Risk in Cirrhosis. Am J Gastroenterol. 2018; 113(8): 1177–86.

32. Algorithm for the MX of AVH in pts with LC *Any of the following: varix spurting blood, varices with overlying clot or with white nipple sign, varices and no other lesion that would explain hemorrhage. **A short-term course (10 days) of PPI may reduce the size of post-banding ulcers. Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 32 /40 Endoscopic procedures

33. Endoscopic procedures 33 Endoscopic sclerotherapy (ESL) was the first available endoscopic therapy for bleeding varices. It involves the injection of a sclerosant agent (100% ethanol, ethanolamine, polidocanol or sodium tetradecyl sulfate) into or adjacent to a varix with the goal of obliteration through irritation and thrombosis. Endoscopic variceal band ligation (EBL) is an attractive first-line therapy because of its improved efficacy and complication profile compared with ESL. On the basis of equal or superior efficacy in initial hemostasis, improved rebleeding rate, ↓ complication rates and possible mortality benefit, EBL should replace ESL as first-line endoscopic treatment. Other viable techniques for hemostatic control include endoscopic clip. Cyanoacrylate glue injection is generally reserved for GV treatment. Previous small studies [1] have shown its effectiveness in EV; however, serious complications including distal embolization causing stroke, pulmonary embolus and mesenteric thrombosis have limited its use. Feretis C, Tabakopoulos D, Benakis P, Xenofontos M, Golematis B. Endoscopic hemostasis of esophageal and gastric variceal bleeding with Histoacryl . Endoscopy. 1990;22:282–4. Limitations of EVL are: 1) Small varices cannot be obliterated after a few sessions of EVL due to technical difficulty. 2) Varices tend to recur because of the persistence of perforating veins and paraesophageal collaterals.

34. Gross M, Schiemann U, Mulhofer A, Zoller WG. Meta-analysis: Efficacy of therapeutic regimens in ongoing variceal bleeding. Endoscopy. 2001;33:737–46. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med. 1995;123:280–7. 34 EBL ESL Initial hemostasis 80 to 100 * 76 to 92 Rebleeding 6 to 30 † 16 to 53 Mortality 19 at 30 days ‡ 35 at 30 days Contraindications Heavily scarred mucosa from previous treatments Previous deep ulcerations from sclerotherapy Complications 5 % Esophageal ulcer Bacterial peritonitis 29 % Aspiration, Empyema, ARDS Esophageal ulcer, Esophageal stricture Perforation, Peritonitis, Mediastinitis Multiband six shooter Tetradecyl 2 mL vial (60 mg) Data from references 1,2 * OR 1.14, 95% CI 0.44 to 2.90 (versus sclerotherapy); † OR 0.52, 95% CI 0.37 to 0.74 (versus sclerotherapy); ‡ OR 0.67, 95% CI 0.46 to 0.98 (versus sclerotherapy); Beta-blockers should not be used in the acute setting as they will decrease blood pressure and will blunt a physiologic increase in HR a/with bleeding.

35. To assess the clinical efficacy of combination therapy (pharmacotherapy and EVL)) compared with monotherapy ie pharmacotherapy, EVL, or TIPS alone in the prevention of rebleeding and mortality. M-A of ten studies involving 1076 pts.[1] Zhang et al. Combination therapy versus pharmacotherapy, endoscopic variceal ligation, or the transjugular intrahepatic portosystemic shunt alone in the secondary prevention of esophageal variceal bleeding: a meta-analysis of randomized controlled trials. Oncotarget . 2017 Aug 22; 8(34): 57399–57408. D’Amico G. Esophageal Varices: From Appearance to Rupture; Natural History and Prognostic Indicators. In: Groszmann RJ, Bosch J, editors. Portal Hypertension in the 21st Century. Dordretch , the Netherlands: Kluwer Academic; 2004. pp. 147–154. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis. 1999;19:475–505. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet. 2003;361:952–954. 35 Regarding overall mortality , combination therapy was as effective as EVL, pharmacotherapy, and TIPS; RR = 0.62, 95% CI: 0.36-1.08, RR=1.05, 95% CI: 0.68-1.63, and RR=1.39, 95% CI: 0.92-2.09, respectively). For rebleeding ; combination therapy was more effective than EVL and pharmacotherapy alone (RR=0.57, 95% CI: 0.41-0.79, and RR=0.65, 95% CI: 0.48-0.88), whereas TIPS was more effective than combination therapy (RR=9.42, 95% CI: 2.99-29.65). TIPS was recommended as the first choice of therapy in the secondary prevention of esophageal variceal bleeding . Pts who survive an episode of AVH are at ↑ risk of rebleeding and death. The median rebleeding rate in untreated individuals is approx 60% and the mortality rate is 33% within 1-2 years of the hemorrhage [2-4].

36. Balloon tamponade 36 Balloon tamponade, given the high incidence of its severe adverse events, should only be used in refractory oesophageal bleeding , as a temporary ‘‘bridge’’ (for a maximum of 24 h) with intensive care monitoring and considering intubation, until definitive treatment can be instituted. Visual and text description link: https://first10em.com/balloon-tamponade-of-massive-gi-bleeding/

37. Use of self-expandable metal stents 37 Data suggest that self-expanding covered oesophageal metal stents may be as efficacious and a safer option than balloon tamponade in refractory EVH. Visual description link: https://www.youtube.com/watch?v=N4Eta8tdmj4 SX-Ella Danis stent

38. Algorithm for the MX of AVH in pts with LC *Any of the following: varix spurting blood, varices with overlying clot or with white nipple sign, varices and no other lesion that would explain hemorrhage. **A short-term course (10 days) of PPI may reduce the size of post-banding ulcers. Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 38 /40 Risk Stratification

39. Algorithm for the MX of AVH in pts with LC ***Excluding pts >75 years old or who have HCC outside Milan criteria, creat of at least 3 mg/dL, previous combination pharmacological plus endoscopic treatment to prevent re-bleeding, bleeding from isolated gastric or ectopic varices, recurrent HE, pulmonary HTN, or heart failure or a combination of these. †Patient should not be discharged on prophylactic antibiotic (consider discontinuing at same time as vasoactive drugs). Zanetto A, et al. Management of acute variceal hemorrhage. F1000Research 2019, 8(F1000 Faculty Rev):966 39

40. Treatment for the prevention of Recurrent EVH 40

41. β- Adrenergic Blocking Drugs NSBB have been used extensively in the prevention of VH. Only nonselective β-blockers should be administered because β1-blockade alone decreases only cardiac output, whereas β2-blockade inhibits splanchnic vasodilatation. Unopposed effect of alpha-1 adrenergic receptors leads to splanchnic vasoconstriction The result of β2-blockade is decreased PBF, which reduces PP. The nonselective β-blockers available are nadolol , propranolol, and timolol . β-Blockers are most effective when they reduce the HVPG to < 12 mm Hg, or by 20% from the baseline. Studies have demonstrated that when β-blockers are used to prevent primary bleeding, they can reduce the risk of esophageal hemorrhage by up to 40% to 50% .[1] Approx 15% of pts have CIs to β-blocker use, including congestive heart failure, severe bronchial asthma, or severe COPD, advanced heart blocks, as well as severe aortic stenosis and PVD . Side effects that limit use of β-blockers are mainly fatigue, lightheadedness, nightmares, and erectile dysfunction. Wilbur K, Sidhu K. Beta blocker prophylaxis for patients with variceal hemorrhage. J Clin Gastroenterol. 2005;39(5):435-440. doi:10.1097/01.mcg.0000159222.16032.98

42. Combined α- and β-Adrenergic Blockers Carvedilol is a NSBB which, in addition, has alpha vasodilatory effects by blockade of the α-receptor. Blockade of the α-receptor decreases intrahepatic vascular resistance, which results in a decrease in PP. Carvedilol has, in addition, antioxidant, and antiproliferative effects .

43. Sec prophylaxis in pts with refractory ascites In pts with cirrhosis and RA, NSBB (propranolol, nadolol) should be used cautiously with close monitoring of blood pressure, serum sodium and serum creatinine. Until randomized trials are available NSBB should be reduced/discontinued if a pt with RA develops any of the following events: Systolic blood pressure <90 mmHg Hyponatremia (<130 mEq /L) Acute kidney injury 43

44. 44

45. 45

46. 46 Valenzuela JE, Schubert T, Fogel RM, et al. A multicenter, randomized, double-blind trial of somatostatin in the management of acute esophageal varices. Hepatology. 1989;10:958–61. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D’Heygere F, McIntyre N. Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Gastroenterology. 1990;99:1388–95. Gotzsche PC, Gjorup I, Bonnen H, Brahe NE, Becker U, Burcharth F. Somatostatin v placebo in bleeding oesophageal varices: Randomised trial and meta-analysis. BMJ. 1995;310:1495–8. Hadengue A. Somatostatin or octreotide in acute variceal bleeding. Digestion. 1999;60:31–41. Sung JJ, Chung SC, Lai CW, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage . Lancet. 1993;342:637–41. Jenkins SA, Shields R, Davies M, et al. A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage . Gut. 1997;41:526–33. Cales P, Masliah C, Bernard B, et al. Early administration of vapreotide for variceal bleeding in patients with cirrhosis. N Engl J Med. 2001;344:23–8.

47. 47 D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: A meta-analytic review. Hepatology. 1995;22:332–54. Saari A, Klvilaakso E, Inberg M, et al. Comparison of somatostatin and vasopressin in bleeding esophageal varices. Am J Gastroenterol. 1990;85:804–7. Tsai YT, Lay CS, Lai KH, et al. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding esophageal varices. Hepatology. 1986;6:406–9. Gimson AE, Westaby D, Hegarty J, Watson A, Williams R. A randomized trial of vasopressin and vasopressin plus nitroglycerin in the control of acute variceal hemorrhage. Hepatology. 1986;6:410–3. Ioannou GN, Doust J, Rockey DC. Systematic review: Terlipressin in acute oesophageal variceal haemorrhage . Aliment Pharmacol Ther . 2003;17:53–64. Escorsell A, Ruiz del Arbol L, Planas R, et al. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: The TEST study. Hepatology. 2000;32:471–6.

48. Thoracic Esophagus Abdominal Esophagus INF THYROID V Superior Phrenic V IVC Left gastric Vein Post branch terminates by joining the AV, the right posterior bronchial vein, or the venous plexus on the surface of the right bronchus. Paraesophageal veins are present on the side of esophagus and are connected with the posterior branch of the LGV Inf Phrenic vein BRONCHIAL V PULMONARY V PV Drains the cardiac region POST branch of LGV ANT branch of LGV AV HAV Cervical Esophagus SVC Venous drainage of esophagus

49. Notes of previous slide The esophagus is a 25-cm long muscular tube that connects the pharynx to the stomach. The esophagus extends from the lower border of the cricoid cartilage (at the level of the sixth cervical vertebra) to the cardiac orifice of the stomach at the side of the body of the 11th thoracic vertebra. The esophagus has 3 constrictions in its vertical course, as follows: The first constriction is at 15 cm from the upper incisor teeth, where the esophagus commences at the cricopharyngeal sphincter; this is the narrowest portion of the esophagus and approximately corresponds to the sixth cervical vertebra The second constriction is at 23 cm from the upper incisor teeth, where it is crossed by the aortic arch and left main bronchus The third constriction is at 40 cm from the upper incisor teeth, where it pierces the diaphragm; the lower esophageal sphincter (LES) is situated at this level . The esophagus has been subdivided into 3 portions , as follows: The cervical portion extends from the cricopharyngeus to the suprasternal notch The thoracic portion extends from the suprasternal notch to the diaphragm The abdominal portion extends from the diaphragm to the cardiac portion of the stomach. The venous blood from the E drains into the submucosal plexus which in turn drains into the periesophageal venous plexus . From this plexus, EV arise in a segmental manner, following the arterial supply. Ultimately the dense submucosal plexus drains into the SVC [1]. The venous drainage of thoracic esophagus to systemic veins occurs mainly through the azygos (AV) and hemiazygos venous system(others intercostal, and bronchial veins ). The drainage to AV caudal to the arch of the AV occurs by eight to ten veins, which drain from right border of esophagus to join the medial aspect of AV. The veins on left side of esophagus drain into hemiazygos veins. Partial drainage of the esophagus also occurs into bronchial and pulmonary veins. The bronchial vein ultimately drains into AV or pulmonary veins. The venous drainage of abdominal esophagus occurs predominantly to the left gastric vein (LGV) a tributary of the portal venous system and partly to IVC via superior and inferior phrenic veins. As the esophagus pierces the diaphragm, several small esophageal veins join the superior and inferior phrenic veins, which drains the diaphragm and abdominal esophagus into the IVC. 49

50. Chikimora et al 1 studied the correlation between angiographic vascular patterns and endoscopic findings of EV & GV by performing percutaneous transhepatic portography and concluded that the portal collateral system was divided into two systems: the portoazygos venous system and the portophrenic venous system . The former contributed to the formation of EV & cardiac varices and the latter to the formation of IGV located at the fundus . The left gastric vein participated as bld supply in 70% of the IGV and in 100% of EV . The posterior gastric vein participated as bld supply in 70% of the IGV and in 24% of EV. The main blood drainage routes of IGV were gastrorenal shunt (85%), gastrophrenic shunt (10%), and gastropericardiac shunt (5%). Chikamori F, Shibuya S, Takase Y, Ozaki A, Fukao K. Transjugular retrograde obliteration for gastric varices. Abdom Imaging. 1996;21(4):299–303 IVC

51. Surgery There are 2 basic types of operations: those that derive blood flow from the portal venous axis ( shunt operations ) and those that do not ( nonshunt operations ). Shunt operations can be categorized as Nonselective (if they derive all portal blood flow to the inferior vena cava bypassing the liver, such as portacaval shunt [PCS]), and Selective (if they are intended to at least partly preserve the portal blood flow to the liver, such as the distal splenorenal shunt [DSRS] or the calibrated small-diameter portacaval H-graft shunt ). However, it is now accepted that the selectivity of these shunts is never completely achieved or is lost during follow-up,[1] and probably for these reasons, no major differences in clinical outcomes among these 2 types of shunt are found at medium- or long-term follow-up .[2] Nonshunt operations generally include esophageal transection or devascularization of the gastroesophageal junction .[3] Belghiti J, Grenier P, Nouel O, et al. Long-term loss of Warren’s shunt selectivity. Angiographic demonstration. Arch Surg 1981;116(9):1121–4. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a metaanalytic review. Hepatology 1995;22:332–54. Terblanche J. The surgeon’s role in the management of portal hypertension. Ann Surg 1989;209(4):381–95.