Medical Management of Upper GI Bleeding

– The EvidenceDr Nola McPherson ED registrar SCGH 2014

Learning Objectives

Background: acute upper GI bleeding (UGIB)

Review MAJOR CAUSES in adults

(Briefly) review general management

Look at the EVIDENCE for specific MEDICAL THERAPIES used in management

Background UGIB

Common medical emergency with associated high morbidity, mortality(6-11%)* and medical expenditure

Most commonly presents with haematemesis and/or melena (much less commonly with haematochezia – 3x higher risk of death*)

Requires rapid assessment (particularly evaluation of haemodynamic stability) and then prompt multi-team management

* Source: Cameron P, Jelinek G, Kelly AM, Murray L, Brown A. Textbook of Adult Emergency Medicine. 3rd Edition. Churchill Livingston Elsevier 2009

Bleeding Manifestations

Haematemesis = bleeding proximal to Ligament of Treitz

Frank bloody emesis vs coffee ground

Melena = majority due to bleeding proximal to Ligament of Treitz, remainder from small bowel or right side of LI

Haematochezia = usually in lower GIT bleed, only if massive UGIB

Factors Predictive of Upper GI bleed*

Melena on PR examination (LR 25)

Blood or coffee ground vomit on NG lavage (LR 9.6)

Ratio of blood urea nitrogen to creatinine >30 (LR 7.5)

Self reported history of melena (LR 5.1-5.9)

Blood clots seen in stool (LR 0.05)

* Source: Srygley FD, Gerardo CJ, Tran T, Fisher DA. Does this patient have a severe upper gastrointestinal bleed? JAMA 2012; 307:1072

Assessment

Aims

assess severity of bleed

identify potential cause

identify co-morbidities that may alter management

decisions

Factors Predictive of a Severe Bleed

History

orthostatic dizziness, confusion, angina, severe palpitations

Examination

tachycardia, orthostatic hypotension or supine hypotension (even worse), cold/clammy peripheries

Bedside and Laboratory Investigations

Hb <80 g/L, high Ur:Cr ratio, high red blood found on NG lavage

Mortality/Morbidity Factors*

Advanced age

Cause of the bleed (particularly varices)

Presence of shock

Fresh bright red blood

Low Hb

Re-bleed presentation

Comorbid disease

Endoscopic findings

*Source: http://lifeinthefastlane.com/ebm-upper-gi-haemorrhage/

Ulcerative or Erosive Disease

Peptic Ulcer Disease*MOST COMMON CAUSE

UGIB*

Idiopathic

Drug induced Aspirin NSAID (approx doubles risk)

Infectious H.pylori, CMV, HSV

Stress induced ulcer (burns, major trauma, sepsis, hypotension, HI)

Zollinger-Ellison Syndrome

Ulcerative or Erosive Disease

Oesophagitis

Peptic

Infectious C. albican, CMV, HSV miscellaneous

Pill induced alendronate tetracycline quinidine KCL aspirin NSAID

Portal HypertensionOesophageal Varices

Gastric Varices

Duodenal Varices

Portal Hypertensive Gastropathy

Large amounts of dark venous blood…

Arterial, Venous or Other Vascular MalformationsIdiopathic angiomas

Hereditary haemorrhagic telangectasia

Dieulafoy’s Lesion

Gastric Antral Vascular Ectasia

Radiation-induced telangiectasia

Blue rubber bleb nevus syndrome

Traumatic or Post SurgicalMallory-Weiss Tear (classic N+V then bleeding in 1/3) Post surgical anastomosisFB ingestion Post gastric/duodenal polypectomyAortoenteric fistula (Hx aortic surgery + bright red haematemesis + haematochezia)

GIT TumoursBENIGN: leiomyoma, lipoma, polyps

MALIGNANT: adenocarcinoma, mesenchymal neoplasm, lymphoma, Kaposi sarcoma, carcinoid, melanoma, metastatic tumour

General Management

General Management Principles

1. supplemental oxygen

2. crystalloid/colloid fluid resuscitation

3. +/- blood transfusion

4. consider correcting coagulopathy (?benefit vs risk)

5. medical management

6. endoscopic (pretreat with erythromycin) / embolisation / surgical management

General Management

Blood Transfusion

consider on individual basis (particularly comorbidities)

indication: Hb <70 g/L (except unstable CHD aim Hb > 90 g/L)1-3

avoid transfusing patients with suspected variceal bleeding to Hb >100 g/L (portal P may worsen bleeding)4, 5-8

give one unit FFP for each four units of packed RBC transfused9

General Management

Consider reversal of coagulopathy (in those actively bleeding)

FFP if INR >1.5 or platelets if count <50 x 109/L

simultaneous replacement + scope if INR <3delay scope until INR <3 if it is initially

higher10

Consider platelet transfusion if life threatening bleeding and taking antiplatelet agents eg aspirin or clopidogrel

If stent or ACS – recommend discuss with cardiologist prior to stopping antiplatelet agent or transfusing platelets11

Medical Management

Acid Suppression

Proton pump inhibitor

H2 R antagonists

Somatostatin Analogue

Octreotide

Other

Terlipressin

Antibiotics

Tranexamic acid

Acid Suppression

Proton Pump Inhibitor (PPI) / H2 Receptor Antagonist

Recommended Practice (Up to Date 2014):12

Give PPI (empirically) to all patients with acute UGIB: esomeprazole or pantoprazole: 80mg IV bolus, followed by 8mg/hour IVI (continued for 72 hours)

Start PPI at presentation (often don’t know source of bleeding)

Once source known (and treated), decision can be made before discharge home if PPI needs to be continued

*note: omeprazole most extensively studied, esomeprazole & pantoprazole PROBABLY acceptable alternatives

Acid Suppression

Evidence?

Meta analysis (2002): Pharmacotherapies for Non Variceal UGIB13,14 :

PPI (IVI) significantly reduces rate of rebleeding compared to H2 R antagonists or placebo

H2 R antagonists had only modest effects in bleeding gastric ulcers and no longer recommended15:

- reduced rebleeding by 7.2%

- reduced surgery by 6.7%

- reduced mortality by 3.2%

Acid Suppression

Evidence cont?

Peptic Ulcers:

PPIs (oral and IV) have additional benefits16,17:

decrease LOHS

decreased need for blood transfusion (in those with high risk ulcers treated with endoscopic therapy)

MAY promote haemostasis in other, non ulcer, lesions

Acid Suppression

However, NO demonstrable effect on all cause mortality

What we know (oops!) think18:

Asians patients likely benefit best from PPI (related to drug metabolism and ability to raise intragastric

pH)

PPI may decrease rate rebleeding, LOHS, need for blood transfusion but likely doesn’t effect mortality

Unfortunately no good data to guide us on best route of administration or dose

Oral dose needs to be at least double std clinical dose

Acid Suppression

What do we know about the timing of administration*??

If given PPI pre – endoscopy: reduces high risk stigmata and the need for endoscopic therapy (OR 0.67)

If given PPI post – endoscopy: reduces risk of requiring surgery, risk of rebleeding and death in high risk patients (RR 0.43, 0.4, 0.41 respectively)

---------------------------------------------------------------------------------------------*Source: http://lifeinthefastlane.com/ebm-upper-gi-haemorrhage/

References: 1. Lau J, Leung W, Wu J et al. Omeprazole before endoscopy in patients with

gastrointestinal bleeding. NEJM 2007; 356:1631- 40.2. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic

ulcer bleeding. Cochrane Database Syst Rev 2006;1:CD002094. [2006 Reference] [2010 Reference]

Somatostatin Analogue

Octreotide

Recommended Practice (Up To Date 2014)12:In suspected or known cases of variceal bleeding, give octreotide 20-50 mcg bolus followed by 25-

50 mcg/hr IVI

may also reduce risk of bleeding due to nonvariceal causes19

(however NOT recommended for routine use in these circumstances – but can be used as an adjunct in some cases)

MOA in this setting: reduces splanchnic arterial blood flow (via vasoconstriction) and portal venous pressure (while still maintaining systemic BP and cardiac output)

Somatostatin Analogue

Octreotide Indications

Suspected or known variceal bleeding

controls bleeding in 74-92% cases18

comparable to injection sclerotherapy and vasopressin for bleeding control and survival, however, with less SE18

reduces rebleeding, blood transfusion requirement and surgery

does NOT reduce mortality significantly (RR 0.80, 95% CI 0.63-1.01)20

Somatostatin Analogue

Octreotide Indications continued….

(Some) bleeding peptic ulcers18: may be reduction in rebleeding may be reduction in need for subsequent surgery NO effect on mortality NOT routinely given, consider if high risk (to avoid the above complications) OR delay until emergency endoscopy

Vasopressin Analogue

Terlipressin

Recommended Practice21:in suspected or known cases of variceal bleedinggive 2mg bolus IV injection (2mg 6 hourly for 24 hours,

then 1mg 6 hourly for 24 hours if bleeding stabilised, then stop)

34% relative risk reduction in mortality

Systematic review has shown NO difference between21: - terlipressin and somatostatin treatment- terlipressin and endoscopy therapy

MOA: synthetic analogue of vasopressin with fewer SE, vasoactive, specificity for splanchnic vessels causing vasoconstriction and reduction in portal pressure

‘Other’ Medical Treatments

Antibiotics

Recommended Practice (Up to Date 2014)12:patients with cirrhosis and UGIB (what ever the

cause) – 20% will have a bacterial infection, further 50% will develop one while in hospital (assoc HIGH mortality)

give ceftriaxone, quinolone or amoxyicillin-clavulanate

‘Other’ Medical Treatments

Evidence?

Prophylactic antibiotics in patients with cirrhosis + UGIB have been shown to 12 :

reduce infectious complications

decreased mortality

may decrease risk of rebleeding from oesoph varices

Timing? benefits shown when given both before and after endoscopy (before preferred)

‘Other’ Medical Treatments

Tranexamic Acid

Recommended practice (Up To Date 2014)12 :NO role in medical management of UGIB

Evidence?

A meta analysis of 7 RCTs found in those patients treated with antiulcer and /or endoscopy for UGIB (the mainstay treatment), tranexamic acid did not provide any additional beneficial effect22

MOA: Anti fibrinolytic agent which competitively inhibits activation of plasminogen to plasmin (plasmin degrades fibrin clots)

Summary

Careful history and examination important – consider source, assess severity, identify comorbid condition, look for signs that indicate complications

Blood transfusion for12:• Haemodynamic instability despite

crystalloid resusc (at least 2L)• Hb < 70 g/L in low risk patients• Hb <90 g/L in high risk (elderly, CAD,

COPD)• Give FFP for coagulopathy (IRN>1.5, PTT

3 sec greater then control)• Give platelets if < 50 x109 /L or platelet dysfunction (chronic aspirin therapy)

Summary

ALL patients with acute upper GI bleeding should be treated at presentation with PPI until source of bleeding is known

Majority of existing studies use omeprazole, we SUSPECT that other PPIs offer the same benefit (?dose ?route)

Evidence PPI in peptic ulcers (major cause of UGIB) reduces most things (!) EXCEPT mortality

(however high risk patients may have improved mortality rates if

PPI given post endoscopy) H2 R antagonists are no longer recommended

Summary

Patients who present with UGIB and have known cirrhosis should have antibiotics before endoscopy

Summary

Patients with known or suspected gastro - oesophageal variceal bleed should have:

octreotide (bolus and then IVI) PLUS antibiotics

Avoid blood transfusing to Hb>100 g/L

OR

terlipressin boluses six hourly PLUS antibiotics

*note: octreotide remains the therapy of choice18

Questions?

References

1. Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol 2012; 107:345

2. Duggan JM. Gastrointestinal hemorrhage: should we transfuse less? Dig Dis Sci 2009; 54:1662

3. Qaseem A, Humphrey LL, Fitterman N, et al. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2013; 159:770

4. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11

References

5. 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; 9:808

6. Cerqueira RM, Andrade L, Correia MR, et al. Risk factors for in-hospital mortality in cirrhotic patients with oesophageal variceal bleeding. Eur J Gastroenterol Hepatol 2012; 24:551

7. Krige JE, Kotze UK, Distiller G, et al. Predictive factors for rebleeding and death in alcoholic cirrhotic patients with acute variceal bleeding: a multivariate analysis. World J Surg 2009; 33:212

References

8. McCormick PA, Jenkins SA, McIntyre N, Burroughs AK. Why portal hypertensive varices bleed and bleed: a hypothesis. Gut 1995; 36:100

9. Maltz GS, Siegel JE, Carson JL. Hematologic management of gastrointestinal bleeding. Gastroenterol Clin North Am 2000; 29:169.

10. Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. Am J Gastroenterol 2007; 102:290.

11. ASGE Standards of Practice Committee, Anderson MA, Ben-Menachem T, et al. Management of antithrombotic agents for endoscopic procedures. Gastrointest Endosc 2009; 70:1060.

References

12. Saltzman, JR. Approach to acute upper gastrointestinal bleeding in adults. In: UpToDate, Feldman, M (Ed), UpToDate, Waltham, MA, 2014

13. Imperale TF. Birgisson S. Somatostatin or octreotide compares with H2-antagonists and placebo in the management of acute non variceal upper gastrointestinal haemorrhage: a meta-analysis. Annals of Internal Medicine 1997; 127: 1062-1071

14. Ioannou GN, Doust J, Rockey DC. Systemic review: terlipressin in acute oesophageal variceal haemorrhage. Alimentary Pharmacology and Therapeutics 2003; 17: 53-64

15. Kwan V, Norton ID. Endoscopic management of non-variceal upper gastrointestinal haemorrhage. Australia and New Zealand Journal of Surgery 2007; 77: 222-230

References

16. Chan WH, Khin LW, Chung YF, et al. Randomized controlled trial of standard versus high-dose intravenous omeprazole after endoscopic therapy in high-risk patients with acute peptic ulcer bleeding. Br J Surg 2011; 98:640

17. Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology 1978; 74:38

18. Cameron P, Jelinek G, Kelly AM, Murray L, Brown A. Textbook of Adult Emergency Medicine. 3rd Edition. Churchill Livingston Elsevier 2009.

References

19. 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.

20. Gøtzsche PC, Hróbjartsson A. Somatostatin analogues for acute bleeding oesophageal varices. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD000193.

21. Ripoll C, Banares R, Beceiro I, et al. Comparison of transcatheter arterial embolisation and surgery for treatment of bleeding peptic ulcer after endoscopic treatment failure. Journal of Vascular and Interventional Radiology 2004; 15; 447-450.

References

22. Gluud LL, Klingenberg SL, Langholz E. Tranexamic acid for upper gastrointestinal bleeding. Cochrane Database Syst Rev 2012; 1:CD006640.

Glasgow-Blatchford Score