The future of GI bleeding in the ICU by Dr Paul Young
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This document discusses several studies related to the use of tranexamic acid (TXA) and stress ulcer prophylaxis in gastrointestinal bleeding and intensive care patients. It summarizes the EXARHOSE trial which will examine the effects of TXA on hemorrhage control in cirrhotic patients with GI bleeding. It also summarizes the PEPSITIC trial, a large cluster randomized trial comparing proton pump inhibitors to H2 receptor blockers for stress ulcer prophylaxis in ICU patients. Finally, it provides an overview of the proposed REVIS trial which would examine IV pantoprazole for stress ulcer prophylaxis in mechanically ventilated ICU patients.
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The future of GI bleeding in the ICU by Dr Paul Young
- 1. The future of GI bleeding Paul Young
- 2. “Prediction is difficult, especially about the future” Niels Bohr
- 3. 1. We will know whether or not to use TXA for patients with GI bleeding
- 5. Number 1: GI bleeding is a common medical emergency that causes substantial mortality worldwide
- 6. Number 2: Mortality is four times higher in patients who rebleed
- 7. Number 3: Rebleeding occurs in 10% of patients with non-variceal bleeding and up to 25% with variceal bleeding
- 8. Number 4: Fibrinolysis may precipitate rebleeding by promoting clot breakdown
- 10. B. How TXA works
- 11. TXA reduces clot breakdown by inhibiting the action of plasmin.
- 12. RR: 0.61, 95% CI: 0.42-0.89
- 15. Pragmatic, randomised, double blind, placebo controlled trial among 8,000 patients with significant gastrointestinal bleeding. DESIGN
- 16. To determine the effect of early administration of TXA on mortality in patients with acute gastrointestinal bleeding. AIM
- 17. Clinically significant acute GI bleeding Equipoise about TXA No exclusions ELIGIBILITY
- 18. death in hospital within 28 days of randomisation PRIMARYOUTCOME
- 19. • Re-bleeding • Need for surgery or radiological intervention • Blood product transfusion • Thromboembolic events • Other complications • Days spent in intensive care unit or high dependency unit SECONDARYOUTCOMES
- 20. A loading dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation, followed by an intravenous infusion of 3 grams of TXA or placebo (sodium chloride 0.9%) over 24 hours. INTERVENTION
- 22. EXARHOSE trial: efficacy & safety of TXA in cirrhotic patients with acute upper GI bleeding DESIGN
- 23. Double blind, placebo controlled trial among 500 cirrhotic patients with acute upper gastrointestinal bleeding. DESIGN
- 24. Four key points.
- 25. Number 1: Variceal bleeding is the main cause of upper GI bleeding in cirrhotic patients
- 26. Number 2: Cirrhotic patients are often coagulopathic
- 27. Number 3: Bleeding is associated with complications like encephalopathy, bacterial peritonitis, and hepatorenal syndrome
- 28. Number 4: Fibrinolysis may precipitate rebleeding by promoting clot breakdown
- 29. To determine the effect of early administration of TXA on haemorrhage control in cirrhotic patients with acute gastrointestinal bleeding. AIM
- 30. • Age ≥ 18 • Acute upper digestive bleeding (< 24h) • Known or suspected cirrhosis • Absence of contraindications to TXA ELIGIBILITY
- 31. A loading dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation, followed by an intravenous infusion of 3 grams of TXA or placebo (sodium chloride 0.9%) over 24 hours. INTERVENTION
- 32. • Death within 5 days • Bleeding within 2 hrs • Transfusion ≥2 units within 24 hrs • Haemorrhagic shock PRIMARYOUTCOME
- 33. • Mortality out to 1 year • Requirements for transfusion of blood and blood products • ICU & hospital LOS • Proportion requiring liver transplant & TIPS • Hepatic complications (hepatic encephalopathy, AKI, hepatorenal Sx, ascitic fluid infection) • TXA complications (allergy, thrombotic events, seizures) SECONDARYOUTCOMES
- 34. 2. We will know whether to use stress ulcer prophylaxis and what drug to use
- 36. • Around 80% of mechanically ventilated adults in ANZ ICUs are prescribed Stress Ulcer Prophylaxis • Most get a Proton Pump Inhibitor (PPI) but many get a Histamine-2 Receptor Blocker (H2RB) BACKGROUND
- 37. PPIs lower risk of overt upper GI bleeding than H2RBs BACKGROUND
- 38. PPI may be associated with higher risk of nosocomial pneumonia and Clostridium Difficile infection than H2RB BACKGROUND
- 39. • Multi-centre, cluster randomised, crossover, registry-embedded clinical trial • Proton Pump Inhibitors (PPI) vs Histamine- 2 Receptor Blockers (H2RB) for Ulcer Prophylaxis • Invasively mechanically ventilated patients in ICU OVERVIEW
- 41. OBJECTIVES 1.Compare PPI and H2RB 2.Explore the methodology
- 42. PRIMARY OUTCOME • In-hospital all-cause mortality (censored at 90 days)
- 43. SECONDARY OUTCOMES • Clinically significant upper GI bleeding • Clostridium difficile infection • Duration of mechanical ventilation (where data are available) • ICU length of stay
- 44. INTERVENTION • Whole ICUs are randomised to default SUP of: 1st six month period 2nd six month period Either PPI H2RB OR H2RB PPI
- 47. Pragmatic, randomised, double blind, placebo controlled trial among 3,350 acute ICU patients with at least one risk factor for gastrointestinal bleeding. DESIGN
- 48. To determine the effect of IV pantoprazole for stress ulcer prophylaxis on mortality in acute ICU patients at risk of gastrointestinal bleeding. AIM
- 49. Acute ICU patients Aged ≥18 years At risk of GI bleeding ELIGIBILITY
- 50. • Shock • RRT • Invasive ventilation expected to last > 24 hours • Coagulopathy • Anticoagulants • Chronic liver disease GIBLEEDINGRISKFACTORS
- 51. • Contraindications to PPI • GI bleeding during current admission • Organ transplant during current admission • Ongoing daily treatment with PPI or H2RB EXCLUSIONS
- 52. 40mg IV pantoprazole or placebo until death or ICU discharge INTERVENTION
- 53. day 90 all cause mortality PRIMARYOUTCOME
- 54. • Proportion of patients with one or more of the following: 1. Clinically important GI bleeding 2. Ventilator associated pneumonia 3. Clostridium difficile infection 4. Acute myocardial ischaemia in the ICU SECONDARYOUTCOMES
- 55. 1. Proportion with clinically important GI bleeding 2. Proportion with an infectious complication 3. 1 year mortality 4. Ventilator-free days, RRT-free days, circulatory support-free days SECONDARYOUTCOMES
- 56. REVIS
- 57. Pragmatic, randomised, double blind, placebo controlled trial among 4,800 mechanically ventilated ICU patients. DESIGN
- 58. To determine the effect of IV pantoprazole for stress ulcer prophylaxis on mortality in adult ICU patients who are expected to be ventilated the day after tomorrow. AIM
- 59. • Pantoprazole & placebo not considered equally appropriate • Acute GI bleeding, Z-E, Barrett’s, PUD within 8 weeks • >24 hrs treatment with PPI OR HRB during this ICU admission EXCLUSIONS
- 60. 40mg IV pantoprazole or placebo until death, discontinuation of ventilation, or UGIB INTERVENTION
- 61. Proportion of patients with clinically significant upper GI bleeding in ICU PRIMARYOUTCOME
- 62. Overt upper GI bleeding (haematemesis, NG bleeding, melena, hematochezia) PLUS ≥1 of the following in 24 hr: 1. Drop in BP 2. Decrease in Hb of at least 20g/L 3. Need for angio, surgery or endoscopic treatment of bleeding UPPERGIBLEEDING
- 63. 1. Ventilator associated pneumonia 2. Clostridium difficile infection 3. Duration of mechanical ventilation 4. Peak creatinine & requirements for RRT 5. ICU LOS 6. Hospital LOS 7. Day 60 mortality SECONDARYOUTCOMES
Hinweis der Redaktion
- Accounts for tens of thousands of hospital admissions per year in ANZ. Mortality rate is around 10% 60,000 hospital admissions each year in the UK The incidence of gastrointestinal hemorrhage ranges from 50 to 150 per 100 000 population each year. Reported mortality rates range from 11% to 33% for patients admitted primarily due to GI hemorrhage or who developed it as a complication of their hospital stay respectively.
- GI bleeding accounts for 10s of thousands of hospital admissions per year in ANZ 10% presenting to hospital with an upper GI bleed die from it; 15% presenting with a lower GI bleed die from it. GI bleeding is common in low and middle income countries, where patients are usually young
- GI bleeding accounts for 20,000 to 30,000 admissions per year. Around 20% is lower GI bleeding and 80% is upper GI bleeding 60,000 hospital admissions each year in the UK The incidence of gastrointestinal hemorrhage ranges from 50 to 150 per 100 000 population each year. Reported mortality rates range from 11% to 33% for patients admitted primarily due to GI hemorrhage or who developed it as a complication of their hospital stay respectively.
- GI bleeding accounts for 20,000 to 30,000 admissions per year. Around 20% is lower GI bleeding and 80% is upper GI bleeding 60,000 hospital admissions each year in the UK The incidence of gastrointestinal hemorrhage ranges from 50 to 150 per 100 000 population each year. Reported mortality rates range from 11% to 33% for patients admitted primarily due to GI hemorrhage or who developed it as a complication of their hospital stay respectively.
- GI bleeding accounts for 20,000 to 30,000 admissions per year. Around 20% is lower GI bleeding and 80% is upper GI bleeding. The incidence of gastrointestinal hemorrhage ranges from 50 to 150 per 100 000 population each year. Reported mortality rates range from 11% to 33% for patients admitted primarily due to GI hemorrhage or who developed it as a complication of their hospital stay respectively.
- Activation of plasminogen by endogenous plasminogen activators results in plasmin which causes degradation of fibrin (fibrinolysis). Fibrinolysis occurs through lysine binding sites on plasminogen binding to lysine in fibrin. TXA is a lysine analogue which inhibits this binding
- Activation of plasminogen by endogenous plasminogen activators results in plasmin which causes degradation of fibrin (fibrinolysis). Fibrinolysis occurs through lysine binding sites on plasminogen binding to lysine in fibrin. TXA is a lysine analogue which inhibits this binding
- It might help promote clotting and reduce clot breakdown...
- But... Only one trial included endoscopic treatments or PPIs No difference in bleeding-related mortality No difference in surgery or transfusion requirementsOnly one trial included endoscopic treatments or proton pump inhibitors. Five per cent of patients on tranexamic acid and 8% of controls died (RR: 0.61, 95% CI: 0.42–0.89). No significant differences were found on bleeding, bleeding-related mortality, surgery or transfusion requirements. Adverse events were unclearly reported.
- Cause-specific mortality will also be reported
- (deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction) (significant cardiac event, sepsis, pneumonia, respiratory failure, renal failure, liver failure, seizures)
- Cause-specific mortality will also be reported
- GI bleeding accounts for 20,000 to 30,000 admissions per year. Around 20% is lower GI bleeding and 80% is upper GI bleeding 60,000 hospital admissions each year in the UK The incidence of gastrointestinal hemorrhage ranges from 50 to 150 per 100 000 population each year. Reported mortality rates range from 11% to 33% for patients admitted primarily due to GI hemorrhage or who developed it as a complication of their hospital stay respectively.
- witnessed by a physician (based on clinical/biological/radiographic data)
- Cause-specific mortality will also be reported
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- However, several studies have shown an associating between using PPIs could increase the risk of pneumonia and C Diff infection than H2RBs
- Hence the PEPTIC study
- Cause-specific mortality will also be reported
- Cause-specific mortality will also be reported
- (deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction) (significant cardiac event, sepsis, pneumonia, respiratory failure, renal failure, liver failure, seizures)
- (deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction) (significant cardiac event, sepsis, pneumonia, respiratory failure, renal failure, liver failure, seizures)
- Re-EValuating the Inhibition of Stress Erosions and prophylaxis against gastrointestinal bleeding in the critically ill
- Age less than 18 years. Pantoprazole and placebo are NOT considered equally appropriate by the treating clinician. Received invasive mechanical ventilation during this ICU admission for ≥72 hours Patients in who a PPI is indicated due to active bleeding or increased bleeding risk, which we define as patients with acute GI bleeding, severe eosophagitis or peptic ulcer disease within the previous 8 weeks, Zollinger Ellison syndrome, Barrett's oesophagus or any previous admission to hospital because of upper GI bleeding (patients receiving Proton Pump Inhibitor (PPI’s) for an uncertain indication are not excluded). Patients who have received more than 24 hours treatment with a PPI or histamine 2 receptor antagonist (H2RA) during this ICU admission Being treated with or need for dual anti-platelet therapy. Being treated with HIV protease inhibitors atazanavir or nelfinavir Being treated with high dose methotrexate Documented cirrhosis or severe liver disease (for example as indicated by an INR > 5.0 which is due to underlying liver disease) The treating clinician is not committed to continuing life-sustaining therapies at the time of enrolment. Pregnancy. Physician, patient, or substitute decision maker (SDM) declines.
- Cause-specific mortality will also be reported
- Clinically important GI bleeding in ICU censored at 60 days after randomisation
- Secondary outcomes: assessing possible harms of PPIs censored at 60 days after randomisation Ventilator associated pneumonia Clostridium difficile associated infection Peak serum creatinine concentration in ICU censored at 60 days New treatment with renal replacement therapy in ICU censored at 60 days Duration of mechanical ventilation Number of days in ICU Number of days in hospital All-cause in-hospital mortality censored at 60 days Tertiary outcome: indicative of minor or occult bleeding Number of units of packed red cells transfused during index hospital admission censored at 60 days
- https://clinicaltrials.gov/ct2/show/NCT02929563?term=gastrointestinal+bleeding&recr=Open&rank=23 Pediatric Intensive Care Ulcer Prophylaxis Pilot Trial (PIC-UP) https://clinicaltrials.gov/ct2/show/NCT03023189?term=gastrointestinal+bleeding+AND+intensive+care&recr=Open&rank=3 Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding (EXARHOSE) https://clinicaltrials.gov/ct2/show/NCT02718261?term=gastrointestinal+bleeding+AND+intensive+care&recr=Open&rank=4 Sup-Icu RENal (SIREN) https://clinicaltrials.gov/ct2/show/NCT01675856?term=gastrointestinal+bleeding&recr=Open&rank=8 Urgent vs. Early Endoscopy in High Risk Patients With Upper Gastrointestinal Bleeding (UGIB) https://clinicaltrials.gov/ct2/show/NCT01506986?term=gastrointestinal+bleeding&recr=Open&rank=31 Helicobacter Eradication Aspirin Trial (HEAT)
- https://clinicaltrials.gov/ct2/show/NCT02929563?term=gastrointestinal+bleeding&recr=Open&rank=23 Pediatric Intensive Care Ulcer Prophylaxis Pilot Trial (PIC-UP) https://clinicaltrials.gov/ct2/show/NCT03023189?term=gastrointestinal+bleeding+AND+intensive+care&recr=Open&rank=3 Efficacity and Safety of Tranexamic Acid in Cirrhotic Patients Presenting With Acute Upper Gastrointestinal Bleeding (EXARHOSE) https://clinicaltrials.gov/ct2/show/NCT02718261?term=gastrointestinal+bleeding+AND+intensive+care&recr=Open&rank=4 Sup-Icu RENal (SIREN) https://clinicaltrials.gov/ct2/show/NCT01675856?term=gastrointestinal+bleeding&recr=Open&rank=8 Urgent vs. Early Endoscopy in High Risk Patients With Upper Gastrointestinal Bleeding (UGIB) https://clinicaltrials.gov/ct2/show/NCT01506986?term=gastrointestinal+bleeding&recr=Open&rank=31 Helicobacter Eradication Aspirin Trial (HEAT)