Antibiotic Prophylaxis in Acute Upper GI Bleed

1. Antibiotic Prophylaxis in Acute Upper GI Bleed Plus a little on octreotide as well

2. Objectives • Discuss background for why antibiotic prophylaxis for upper GI bleed is an issue. • Review the anatomy of portal hypertension and the development of varices. • Review physical findings which suggest the presence of portal hypertension. • Discuss evidence supporting use of antibiotics in patients with portal hypertension and upper GI bleeding. • Review antibiotics of choice • Group discussion of possible guideline with respect to use of prophylactic antibiotics in upper GI bleed. • Review mechanism of action of octreotide • Brief review of literature supporting use of octreotide in variceal bleeding • Brief review of literature addressing use of octreotide in nonvericeal upper GI bleeding • Review dosing and duration of octreotide. • Group discussion of possible guideline with respect to use of octreotide in upper GI bleed.

3. Case 1 • Case 1 • 58 y/o M with hx of EtOH abuse presents with 1st episode of hematemisis. He has no hospitalizations. He is lightheaded at the time of presentation. He has been drinking “6 beers” a day for more than 20 years. • On exam he has no “spiders”, gynecomastia, palmarerythema, or ascietes. He is guaiac positive. • Should his admission medications include prophylactic antibiotics? • Octreotide?

4. Case 2 • 36 year old male with a history of hepatitis C and alcohol abuse presents with bright red blood per rectum. • On exam he has no “spiders”, gynecomastia, palmarerythema, or ascietes. He is guaiac positive. Prior U/S showed a mostly homogenous liver with a few regenerative nodules. • Should his admission medications include prophylactic antibiotics? • Octreotide?

5. Case 3 • A 65 y/o woman with a history of chronic knee pain from osteoarthirits who takes NSAIDs daily presents with hematemesis. • No history of liver disease nor evidence of liver disease on exam. Her NG lavage has not cleared after 1 liter. • Should her admission medications include prophylactic antibiotics? • Octreotide?

6. Case 4 • 58 year old woman who was previously healthy. Drinks no more than 1 drink of alcohol a day. No history of IVDA. She does take occasional NSAID for knee pain. Presents with hematemesis. NG lavage has not cleared after 1 liter. • On exam she has “spiders” on her chest and shifting dullness on abdominal exam. • Should her admission medications include prophylactic antibiotics? • Octreotide?

7. A brief anatomy review

8. Vascular Changes in Portal Hypertension

9. Pathological anatomy associated with portal hypertension

10. Findings suggestive of portal HTN • History of alcohol abuse alone is not sufficient. • History of prior evidence of liver disease (steatosis or cirrhosis) especially with ongoing risk factors (alcohol or viral hepatitis) is suggestive. • Splenomegalyor ascities • Thrombocytopenia • Ultrasound showing regenerative nodules. • Doppler showing abnormal flow in the portal system. • Lancet; Volume 324, Issue 8397, 4 August 1984, Pages 241-244 – Prospective Evaluation of Alcohol Abuse and Alcoholic Liver Injury in Men as Predictors of Development of Cirrhosis

11. Actual Doppler Report from 1 month ago • “Portal venous system patent and demonstrating hepatopedal flow.” • What does this mean?

12. Why consider antibiotic prophylaxis for variceal bleeding. • 22% of patients with cirrhosis presenting with GI bleeding develop bacterial infections within 48 hours. • Between 35 and 66% develop infections within 7 to 14 days. • Bacterial infections were associated with an increased risk of rebleeding. • Mortality from acute variceal bleeding approaches 20% but increases to > 50% with rebleeding and infection • BleichnerG, Boulanger R, et al. Frequency of infections in cirrhotic patients presenting with gastrointestinal haemorrhage. Br J Surgery 1986;73: 724 – 726. • Bernard B, Cadranel JF, Valla D, Escolano S, Jarlier V, Opolon P. Prognostic significance of bacterial infection in bleeding cirrhotic patients: a propective study. Gastroenterology 1995;108:1828-1834. • Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. II. Clinical prognostic factors. GastrointestEndosc. 1981; 27: 80 – 93 • Goulis J, Armonis A, Patch D, Sabin C, Greenslade L, Burroughs AK. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. HEPATOLOGY 1998;27:1207-1212.

13. Data supporting use of antibiotics in variceal bleeding • Early studies showed that oral, non-absorbable antibiotics given to cirrhotics with GI bleeding reduced the rate of infection, but did not affect mortality. • Subsequent studies showed that IV antibiotics also reduced the rate of infection, but again did not show improved mortality. • RimolaA, Bory F, Teres J, Perez-Ayuso R, Arroyo V, Rodes J. Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology 1985;5(3):463-7. • BlaiseM, Pateron D, Trinchet JC, Levacher S, Beaugrand M, Pourriat JL. Systemic antibiotic therapy prevents bacterial infection in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1994;20(1 Pt 1):34-8. • Bernard B: Grange JD, Khac EN, et al. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding; A meta-analysis. Hepatology 1999; 29:1655.

14. So, is there a mortality benefit? • A Cochrane Review from 2009 showed that administration of antibiotics to cirrhotics with GI bleed was associated with a reduction in mortality – Relative Risk 0.73. • The mortality benefit was identified in studies where the patient was given prophylacitc antibiotics before endoscopy. • Antibiotics given immediately after endoscopy has also been shown to reduce rebleeding, but not mortality. This study was not included in the Cochrane Review. • Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD002907. DOI: 10.1002/14651858.CD002907. • Hou MC, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology, Feb. 27 2004, Vol. 39 Issue 3, 746 – 753.

15. What about Gastric Varices? • There is much less literature on gastric varices. • A 2008 AASLD Guideline recommended that Type 1 gastric varices (which are extensions of esophageal varices) be managed the same as esophageal varices, but did not include the use of prophylactic antibiotics nor the use of octreotide in their recommendations for gastric varices other than Type 1. • Garcia-Tsao G, Sanyal AJ, et al. Prevention and Management of GastroesophagealVarices and Variceal Hemorrhage in Cirrhosis. American Association for the Study of Liver Disease Guidelines. Hepatology. Sept 2007. 922- 938.

16. Which Antibiotics and for how long? • The most extensively studied have been ceftriaxone and norfloxacin. • Ceftriaxone1 gram IV for 5 to 7 days • Norfloxacin 400 mg po bid for 5 to 7 days. • One study demonstrated superiority of ceftriaxone to norfloxacin. • A recent review in the NEJM recommended ceftriaxone if the patient had severe liver disease or had been receiving quinolone prophylaxis for SBP. • FernándezJ, Ruiz del Arbol L, Gómez C, et al. Norfloxacinvsceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049-1056 • Garcia-TsaoG, Bosch J. Management of Varices and Variceal Hemorrhage in Cirrhosis. NEJM March 10, 2010. Volume 362; 823 – 832.

17. How common is the problem at UNMH? • Probably more common than this : • Review of discharge diagnoses for 2009 looking for patients who carried the diagnosis of cirrhosis and GI bleed demonstrated only 50 patients who met the criteria.

18. What about patients who do not have portal hypertension? • This appears to have not been studied. Infections do not seem to be common in patients without portal hypertension – this is likely an effect of the reduction in bacterial load in the stomach and proximal small intestine when compared to the distal esophagus. • Modern Medicine; Volume X, February 1901, Pages 25 – 30 – The Bacteriology of the Stomach

19. Recommendations for Guideline • Antibiotics should be given prior to endoscopy if possible. • Only patients with known portal hypertension or cirrhosis, or patients who are suspected to have portal hypertension or cirrhosis by history or exam should be given prophylactic antibiotics prior to endoscopy. • After endoscopy only patients with evidence of portal hypertension should receive the full course of antibiotic prophylaxis. • Ceftriaxone should be used as the antibiotic of choice initially. (Ciprofloxacin or norfloxacin if unable to take Ceftriaxone.) • When the patient is going home they can be switched to Ciprofloxacin. (Augmentin if unable to take Ciprofloxacin.)

20. What about the use of octreotide?Should it be used in patients without portal hypertension?

21. What is octreotide? • Octreotide is a synthetic analogue of somatostatin. It has a longer half life (80 minutes) than somatostatin (3 min). • It prevents splanchnicvasodilation caused by glucagon and vasoactive intestinal peptide as well as reducing the postprandial splanchnic hyperemia. Through these mechanisms it lowers portal venous flow, hepatic venous pressure gradient, and azygos venous flow – though some of these effects seem transient. The effect on postprandial splanchnic hyperemia lasts up to 48 hours

22. What is the evidence for use of octreotide in variceal bleeding? • Though the evidence supporting the use of octreotide in variceal bleeding is not universally positive, a Cochrane review showed that octreotide was effective at stopping bleeding, but had no mortality benefit. • There was a benefit seen in 5 day success rates (primarily the risk of rebleeding)when octreotide was used in conjunction with variceal ligation – but there was no mortality benefit. • A mortality benefit was seen with terlipressin (which is currently not available in the US). • Gøtzsche PC, Hróbjartsson A. Somatostatin analogues for acute bleeding oesophagealvarices. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000193. DOI: 10.1002/14651858.CD000193.pub3. • Banares R, Albillos A, Rincon D, et al. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: A meta-analysis. Hepatology 2002; 35:609 • Ioannou GN, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD002147. DOI: 10.1002/14651858.CD002147.

23. Has octreotide been shown to be useful for GI bleeds when the patient does not have portal hypertension? • The effects of octreotide are not limited to patients with portal hypertension. • A 1997 meta-analysis showed that either somatostatin or octreotide were superior to H2 blockers in management of acute nonvariceal upper gastrointestinal bleeding. • Data from some of the studies included in this meta-analysis have been called into question. So the routine use of octreotide was not included in the 2003 Nonvariceal Upper GI Bleeding Consensus Guidelines. However, there was a supporting statement suggesting it might be useful in patients with sustained bleeding while awaiting endoscopy. • Clarke DL, McKune A, Thomson SR. Octreotide lowers gastric mucosal blood flow in normal and portal hypertensive stomachs. SurgEndosc. 2003;17:1570–1572. doi: 10.1007/s00464-002-9274-z. • Imperiale TF, Birgisson S. Somatostatin or octreotide compared with H2 antagonists and placebo in the management of acute nonvariceal upper gastrointestinal hemorrhage: a meta-analysis. Ann Intern Med. 1997;127:1062–1071. • Barkun A, Bardou M, Marshall JK., for the Nonvariceal Upper GIBCCG Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med. 2003;139:843–857.

24. What is the current recommendation for use of octreotide in GI bleeders with portal hypertension? • 50 microgram bolus followed by infusion of 50 micrograms per hour for 2 to 5 days. • Sharara A, Rockey D. GastroesophagealVariceal Hemorrhage. NEJM. Volume 345:669-681.

25. Recommendations for Guideline • Octreotide should be used in gastrointestinal bleeding for all patients who have or are suspected to have portal hypertension. • In patients who do not have portal hypertension, octreotide can be used if there is evidence of ongoing bleeding and there is a delay in obtaining endoscopy (these patients should be exclusively in the ICU). • Patients with variceal bleeding demonstrated on endoscopy should receive octreotide for a minimum of 3 days. • There is no clear guideline for patients with portal hypertension who have nonvariceal upper gastrointestinal bleeding with respect to utilization of octreotide.

26. Case 1 • Case 1 • 58 y/o M with hx of EtOH abuse presents with 1st episode of hematemisis. He has no hospitalizations. He is lightheaded at the time of presentation. He has been drinking “6 beers” a day for more than 20 years. • On exam he has no “spiders”, gynecomastia, palmarerythema, or ascietes. He is guaiac positive. • Should his admission medications include prophylactic antibiotics? • Octreotide?

27. Case 2 36 year old male with a history of hepatitis C and alcohol abuse presents with bright red blood per rectum. On exam he has no “spiders”, gynecomastia, palmarerythema, or ascietes. He is guaiac positive. Prior U/S showed a mostly homogenous liver with a few regenerative nodules. Should his admission medications include prophylactic antibiotics? Octreotide?

28. Case 3 • A 65 y/o woman with a history of chronic knee pain from osteoarthirits who takes NSAIDs daily presents with hematemesis. • No history of liver disease nor evidence of liver disease on exam. Her NG lavage has not cleared after 1 liter. • Should her admission medications include prophylactic antibiotics? • Octreotide?

29. Case 4 • 58 year old woman who was previously healthy. Drinks no more than 1 drink of alcohol a day. No history of IVDA. She does take occasional NSAID for knee pain. Presents with hematemesis. NG lavage has not cleared after 1 liter. • On exam she has “spiders” on her chest and shifting dullness on abdominal exam. • Should her admission medications include prophylactic antibiotics? • Octreotide?