ACUTE VARICEAL BLEEDING MULTIMODAL APPROACH

Transcription

1 FALK symposium. Liver Cirrhosis: from pathophysiology to disease management Dresden, October ACUTE VARICEAL BLEEDING MULTIMODAL APPROACH Professor Andrew K Burroughs Hepato-biliary biliary-pancreatic and Liver Transplantation Unit Royal Free Hospital

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4 White nipple sign varix varix Platelet/fibrin plug Platelet/fibrin plug

5 Prognostic significance of the white nipple sign (Siringo 1989) Prospective study: white nipple no white nipple admissions active bleeding at endoscopy 39% 44% failure to control bleeding 24 hours 11% 24% cumulative at 5 days 39% 49%

6 Diagnosis of upper GI bleeding in cirrhosis Endoscopy as soon as resuscitation adequate It is a high risk endoscopy - adequate support staff (suction) - assess risk of aspiration - pulse oximetry - nasal oxygen - will need endotracheal intubation/ga in several cases Look at fundus, other lesions NB 50% DGH do not have an adequately supported on call system

7 Rapid imaging in UGI bleeding in cirrhosis Establish patency portal vein Look for hepatocellular carcinoma Use ultrasound/ doppler

8 MORTALITY FROM VARICEAL BLEEDING McCormick et al 2001

9 Mortality from variceal bleeding in a single centre (Carbonell 2004) Child Pugh A/B Child Pugh C

10 PROSPECTIVE STUDY OF UPPER GI BLEEDING IN CIRRHOTICS (D Amico 2003) cirrhotics patients 5 day failure Rebleed 5d varices % 4.8% P=0.03 Non-variceal 114 7% 1.8% Deaths 5d 9.2% P= % Rebleed 6w 19% P= % Deaths 6 w 20.8% P= %

11 Acute variceal bleeding Factors associated with failure to control bleeding severity of liver disease (many authors) active bleeding at endoscopy (Ben Ari 1999) portal pressure (Ready 1991, Moitinho 1999) infection (Bernard 1995, Goulis 1998)? haemostasis (? independent of severity of liver disease)

12 PREDICTIVE MODEL for FAILURE to CONTROL ACUTE VARICEAL BLEEDING (BenAri 1999) Continued bleeding 24h / early rebleeding 5 days 385 patients vasoactive drugs sclerotherapy if failure MV analysis: failure to control bleeding 30 days mortality * active bleeding at endoscopy PSE urea (log) bleeding started at hospital haematemesis platelets failure to control bleeding PSE urea (log) bleeding started at hospital pulse PT (log) bilirubin Irrespective of interval from admission * Interaction with Child-Pugh, transfusion need, bleeding in hospital and transfusion need, active bleeding and transfusion need

13 PREDICTIVE MODEL for FAILURE to CONTROL ACUTE VARICEAL BLEEDING (BenAri 1999) Time to failure (hrs) < No failure Number failed to control bleeding % death 30 days 24 % 12 % 21 % 33 % 50 % 6 %

14 Portal Pressure and Variceal Bleeding (Moitinho 1999) Outcome according to HPVG at admission 20 mmhg < 20 mmhg

15 HVPG PREDICTION of 5 DAY FAILURE in ACUTE VARICEAL BLEEDING (Albraldes 2006) 117 patients HVPG measured 48 h ( 4 centres) 18 (15%) failure at 5 days (vasoactive drugs,endoscopic therapy, antibiotics) HVPG 20 mmhg OR 5.2 ( ) Systolic BP 100mmHg OR 3.6 ( ) Non-alcoholic cirrhosis OR 4.0 ( ) c statistic 0.79 HVPG 20 mmhg strongly related to CP (p=0.0002) Child A 33% Child B 57% Child C 84% Without HVPG c statistic 0.8

16 HVPG PREDICTION of 5 DAY FAILURE in ACUTE VARICEAL BLEEDING (Albraldes 2006) Allocation points score % failure Systolic B 100 mm Hg points 8 % Systolic B > 100 mm Hg 0 Non-alcoholic cirrhosis 1 Alcoholic cirrhosis 0 Child B points 39 % Child C 2 p =

17 HVPG and SEVERITY of CIRRHOSIS and SIZE of VARICES (Wadhawan 2006) HVPG mmhg ± ±6.9 19± ± ± ± ±6.2 0 Child A Child B Child C small large bleeders non-bleeders

18 Volume change and HVPG in human cirrhosis 12 cirrhotics 600 ml venesected 600 ml restituted Vlavianos 1999

19 Do you obtain blood cultures routinely in known cirrhotic patients, or those suspected of being so, if presenting with upper GI bleeding? Yes No

20 Frequency of bacterial infection in cirrhosis prospective study (Borzio 2001) In hospital mortality 15% v 7% non infected % fever GI bld jaund asc PSE HCC others admission to hospital

21 ACUTE VARICEAL BLEEDING - PROPHYLACTIC ANTIBIOTICS AND BACTERIAL INFECTIONS

22 ACUTE VARICEAL BLEEDING PROPHYLACTIC ANTIBIOTICS AND MORTALITY

23 Complications of portal hypertension Sepsis Bacterial translocation Renal failure Liver failure

24 RANDOMIZED TRIALS of PROPHYLACTIC vs ON DEMAND ANTIBIOTICS for ACUTE VARICEAL BLEEDING Grade C 22.5% Grade C c. 20% iv ofloxacin 200mg qds 2d iv cefotaxime 1gr tds 7d po ofloxacin 200mg bd 5d Frequency of infection on demand prophylaxis % patients % 15.5% 5 0 Hou 2004 Jun 2006 no evidence infection 3.4% 3.2% consecutive admissions

25 EARLY REBLEEDING in RANDOMIZED TRIALS of PROPHYLACTIC vs ON DEMAND ANTIBIOTICS Frequency of bleeding on demand prophylaxis days 6 weeks Hou2004 Jun.2006 Hou2004 Jun.2006

26 QUINOLONES vs CEPHALOSPORINS in the MANAGEMENT of UPPER GI BLEEDING in CIRRHOSIS Included 33% ASC/PSE/shock/ascites Included 9% 2 of PSE/Bil 3mg+/ severe malnutrition Infections: during hospitalization 10 days % infections quinolones 46 patients 65% varices 24% grade C ceftriaxone±quinolones severe infections total infections quinolones Fernandez 2006 Sabat 1998 Antibiotics given: all<6 hours at 6.8±2.9 hours 111 patients 69% varices 53% grade C ceftriaxone

27 QUINOLONES VERSUS CEPHALOSPORINS FOR MANAGEMENT OF UPPER GI BLEEDING IN CIRRHOSIS Failure to control bleeding < 5 days <24 hours failure to control bleeding ceftriaxone±quinolones quinolones quinolones ceftriaxone Sabat 1998 Fernandez 2006

28 WHICH ANTIBIOTIC FOR PROPHYLAXIS IN UPPER GI BLEEDING IN CIRRHOSIS? IV 3 rd generation cephalosporins Start at admission before endoscopy Active against quinolone resistant bacteria gram negative bacteria non enterococcal streptococci No issue of poor absorption due to bleeding, pseudo-ileus etc. Many cirrhotics receive quinolone prophylaxis Will treat infections already present 20% culture positive at admission 50% of infections in cirrhotics are culture negative

29 MORTALITY and ADRENAL INSUFFICIENCY in CIRRHOTIC PATIENTS with SEPSIS Fernandez 2006 Septic shock (n=25) Hydrocortisone 50 mg qds improved survival compared to historical controls (64% vs 32%, p=0.003) Tsai 2006 Critically ill/severe sepsis (n=101) Adrenal insufficiency in 51.5% - associated with: increased mortality 81% vs 37% bacteraemia

30 FREQUENCY of ADRENAL INSUFFICIENCY in CIRRHOTIC PATIENTS with SEPSIS % Adrenal insufficiency Critically ill/sepsis n= 101 (Tsai 2006) Septic shock n= 25 (Fernandez 2006) % Total < CP 11 > Tsai Total B CP C Fernandez

31 Transfusion Airway Kidneys Electrolytes BAVENO III TAKE CARE IN OGV Coagulation Alcohol withdrawal Resuscitation Encephalopathy Infection Nutrition Oxygen Gastric Varices

32 Treatment strategies used in acute variceal bleeding: randomised trials Vasoactive drugs (±( tamponade) ) v. vasoactive drugs (±( tamponade) ) + sclerotherapy Vasoactive drugs v. sclerotherapy Vasoactive drugs + therapeutic endoscopy v. therapeutic endoscopy Sclerotherapy v. ligation Recombinant factor VII + therapeutic endoscopy v. placebo + therapeutic endoscopy

33 VASOACTIVE DRUGS IN ACUTE VARICEAL BLEEDING ( Cochrane reviews) Patients Studies Mortality 95% CI Early rebleeding failure initial haemostasis Transfusion need Terlipressin (Ioannou 2002) ( ) 0.88) Somatostatin analogues ( Gotzche 2001) ( ) 0.61( ) 1.09) 0.68( ) 0.92) Reduction of 1 unit blood

34 RANDOMISED TRIAL OF SOMATOSTATIN SCHEDULES FOR ACUTE VARICEAL BLEEDING (Moitinho( 2001) Bolus 250µg g 250µgX3 250µgX3 infusion 250µg/hr 250µg/hr 500µg/hr Active bleeding at endoscopy Control bleeding+ 58% 61% 82%* Early rebleeding 25% 15% 15% 6week mortality 33% 26% 7% + assessed at 48hrs *p=0.13 p=0.05 Endoscopic therapy if failure of drug therapy

35 RCT 250 vs 500 mg somatostatin for acute variceal bleeding with sclerotherapy (Palazon 2006) Sclerotherapy and 5 days ST: Patients Initial haemostasis Early rebleeding Early rebleeding Child B or C 6 week mortality 250 mg 29 90% 35% 39% 24% 500 mg 33 85% 15% 13% 15%

36 Early administration of Terlipressin and GTN for GI bleeding in cirrhotics (Levacher 1995) double blind:12hrs placebo terlipressin/gtn /GTN episodes persistent bleeding 28% 17% rebleeding 26% 12% mortality 4% 2% blood:units/patient/hr control of bleeding: all 47% 71%* control of bleeding: varices 42% 78%º 1-2mg T/10mg/24h GTN *p< %: 72%º p=0.017

37 Do you use sclerotherapy at diagnostic endoscopy if oesophageal varices are diagnosed as the source of bleeding? Yes No

38 Acute variceal bleeding Drugs vs sclerotherapy Failure to control bleeding (all papers)

39 Acute variceal bleeding Drugs vs sclerotherapy Mortality

40 Acute variceal bleeding Endotherapy + drugs vs endotherapy Failure to control bleeding

41 Acute variceal bleeding Endotherapy + drugs vs endotherapy Mortality

42 RCT OCTREOTIDE + SCLEROTHERAPY vs SCLEROTHERAPY (Morales 2007) 48 hours octreotide Patients 7 day mortality Rebleeding Mean units transfused ITU support Scl 28 18% 21% % Scl+oct 40 20% 20% %

43 If you see actively bleeding oesophageal varices at diagnostic endoscopy, do you remove the scope and (a) arrange for immediate endotracheal intubation? Yes No (b) attach a ligating device, and pass the scope again and ligate varices? Yes No (c) place balloon tamponade and consider referral? Yes No

44 ACUTE VARICEAL BLEEDING LIGATION vs SCLEROTHERAPY FAILURE to CONTROL BLEEDING

45 ACUTE VARICEAL BLEEDING LIGATION vs SCLEROTHERAPY - MORTALITY

46 RCT LIGATION vs SCLEROTHERAPY (Villaneuva 2006) SOM + SCL SOM + EVL Patients Failure 5 days 24 % * p= % * Child C Failure 5 days 33 % NS 25 % Active bleeding Failure 5 days 24 % NS 18 % Deaths at 5 days 3 % NS 3 % Deaths at 6 weeks 21 % NS 13% * amongst failures 50% died compared to 11 % successes * * HVPG > 16 mm Hg associated with failure

47 Control of variceal bleeding with emergency sclerotherapy (Triantos 2005) % median % 83% 69% 95% 5 trials trials trials trials 1309 S+d v.drugs v. drugs v. S+drugs v. ligation* * At the end of endoscopy

48 ACUTE VARICEAL BLEEDING RCT OF rviia (Bosch 2004) 10/119 6/120 10/116 9/116 variceal bleeders variceal bleeders placebo rfviia placebo rfviia Failure to control acute bleeding (within 24h) Failure to prevent rebleeding (24h - day 5)

49 ACTIVE VARICEAL BLEEDING in CHILD B and C CHIRRHOSIS DOUBLE BLIND PLACEBO CONTROLLED TRIAL of rf.viia Bosch doses <24h Placebo 600mg rfviia 300mg rfviia Patients Failure to control bleeding 8% 9% 8% Failure to prevent rebleeding (24h to 5d) 8% 4% 4% Mortality 5d 13% 12% 5% Mortality 42d 29% 15% 31%

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51 Histoacryl glue Flush biopsy channel with lipiodol Mix 1ml glue with 1-2mls 1 lipiodol Flush sclerotherapy needle with saline Wear glasses/goggles Plentiful supply of needles Preparation Consent?

52 RCT standard endoscopic therapy vs glues Haemostasis: no. 114 Thakeb Feretis Zimmer Sung % scl scl + hist acryl 56 scl scl + hist acryl lig cyano acryl

53 RCT standard endoscopic therapy vs glues rebleeding: no. 114 Thakeb Feretis Zimmer Sung % scl 25 scl + hist acryl scl glue lig cyano acryl

54 RCT standard endoscopic therapy vs glues mortality: Thakeb no Feretis Zimmer Sung % scl 4 scl + hist acryl 9 scl 14 glue 28 lig cyano acryl

55 Acutely bleeding Gastric Varices High early rebleeding with sclerotherapy and ligation (Jansen 1995, Tan 2006) Glues effective (Hou Hou 1998, Sarin 2002, Greenwald 2003, Milson 2003, Tan 2006 ) TIPS effective (Chau 90% control Chau 1998, Barange 1999, Azoulay 2001)

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57 RCT BAND LIGATION vs N BUTYL-2 CYANOACRYLATE (Tan 2006) gastric varices ligation glue Patients Active bleeding controlled 14 of of 15 Rebleeding 44% p< % + Cumulative rebleeding 72% p< % at 3 years + use of ligation was independently associated with rebleeding

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59 RCT TIPS vs CYANOACRYLATE INJECTION for PREVENTION of GASTRIC REBLEEDING (Lo 2007) Patients Rebleeding TIPS (43%) GLUE (59%) Rebleeding gastric varices Survival 4 (11%) same 14 (38%)

60 Sengstaken Blakemore Bridge TIPS Liver Transplant

61 SELF-EXPANDING METAL STENTS TO TREAT ACUTE BLEEDING FROM OESOPHAGEAL VARICES (Hubmann 2006) 15 from 143 patients (+5 referred) new type of stent (Ella-Denis) in % successful deployment radiological screening 100% haemostasis 100% successful endoscopic removal between 2-14 days 20% migration into stomach-endoscopic adjustment no local complications

62 The correct positioning is ensured by a balloon at the end of the set.

63 Course

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65 When sclerotherapy or ligation with vasoactive drugs have failed, do you (a) use tissue adhesives? Yes No (b) refer for TIPS? Yes No

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67 DEFINITION of UNCONTROLLED VARICEAL HAEMORRHAGE at RFH Continued/early variceal rebleeding (within 5 days) despite 2 sessions of therapeutic endoscopy Continued variceal bleeding despite correctly placed balloon tamponade Continued/early gastric or ectopic variceal bleeding despite vasoconstrictor therapy

68 Emergency salvage TIPS for variceal bleeding (Chau 1998) varices oesophageal gastric fundal patients (%Child s C) 84 (75%) 28 (60%) early rebleeding <7 days 11 4 varices 3 (3.5%) 1 (6%) oesophageal ulcer 4 1 PHG 1 1 not identified 3 1 mortality 31 (37%) 12 (43%)

69 Emergency TIPS series: immediate control of bleeding no c.bleed % LaBerge 93 Hang 93 Rubin 95 Jalan 95 Jabour 96 Sanayal 96 Perarnau 97 Banares 98 Gerbes 98 Chau 98 Barange 99 Bizollon 01 Azoulay 01

70 Emergency TIPS series: mortality no mortal. % Hang 93 Helton 93 Jalan 95 Jabour 96 Sanayal 96 Perarnau 97 Banares 98 Gerbes 98 Chau 98 Barange 99 Bizollon 01 Azoulay 01

71 RCT OF EARLY TIPS IN ACUTE VARICEAL BLEEDERS WITH HVPG 20 mmhg (Monescillo 2004) HVPG 20 mmhg ( 24 hr) Patients Non TIPS 26 TIPS 26 Treatment failure 50% 0 12% Transfusion (units) Mortality at 6 weeks 38% 17% o 77% of these (n=10) within 48 hours of admission 38% (n=5) could not receive 2 nd sclerotherapy or TIPS. Predictive accuracy for treatment failure of 20 mmhg - 77% - ROC curve HVPG , Pugh s

72 TIPS technique

73 TIPS technique

74 TIPS technique

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76 Colonic Varices

77 TIPS FOR PORTAL VEIN THROMBOSIS AT RFH Senzolo et al 2005

78 TIPS FOR PORTAL VEIN THROMBOSIS AT RFH Senzolo et al 2005

79 TIPS FOR PORTAL VEIN THROMBOSIS AT RFH Senzolo et al patients portal vein thrombosis - 12 with cirrhosis Total Complete PVT Cavernoma Successful 65% 61% 62% Complications Mechanical thrombectomy 53% * Variceal bleeding in 14, pre OLT 3, Budd Chiari 2, Ascites 5, portal biliopathy 2

80 BLEEDING FROM ECTOPIC VARICES TREATMENT WITH TIPS AND EMBOLISATION (Vangeli 2004) Ectopic variceal bleeding 5% cause of bleeding in cirrhotics Endoscopic treatment is ineffective (especially for rectal varices) Patients Total TIPS 19* Rebleeding Further successful embolisation TIPS alone 12 42% (48h) 80% TIPS + Embolisation 6 28% 100% * 2 technical failure

81 RETROGRADE BALLOON OCCLUSION of GASTRIC VARICES

82 POTENTIAL AREAS of CLINICAL STUDY in ACUTE VARICEAL BLEEDING Prophylactic antibiotics given at admission not after diagnosis High risk of failure to control bleeding - glue as first line therapy - TIPS as first line therapy Assess risks of double intubation - diagnostic endoscopy and then ligation Routine endotracheal intubation in high risk patients - aspiration pneumonia Steroids in infected patients

83 ACUTE VARICEAL BLEEDING BAVENO CONSENSUS IV (2005) blood restitution to 8g/dL prophylactic antibiotic mandatory endoscopy within 12 hours vasoactive drugs before diagnostic endoscopy - maintained 2-5 days - no preference indicated - combined with endoscopic therapy ligation preferred, sclerotherapy not excluded tissue adesive for gastric varices failures use TIPS (covered stents) ATLANTA CONSENSUS (2006)