Case conference

presenter：PGY 張家華

supervisor：林立偉醫師

2013.05.29

Patient profile• 性別:  male• 年齡: 83 y/o• 到院時間: day1 23:25• 到院方式:自家車

• 主訴: 血便/黑便

• 過去病史:高血壓,糖尿病,消化性潰瘍

• 意識: E4V5M6• T/P/R: 36.9/95/18, SpO2:97%

• CC: Tarry stool tonight

• PI:– anorexia for 2 weeks– nausea(‐), vomiting(‐), dizziness(‐)

• Underlying disease – DM– HTN

Physical examination• TPR:36./95/18,  120/55 mmHg

• Consciousness: E4V5M6

• HEENT: conjunctiva pale (mild pale), sclera: icteric ( ‐ )

• CHEST: RHB, bilateral clear BS

• Abdomen: soft , no tenderness

• EXTREMITIES: warm

Initial order• day1 23:30

– IVF: N/S run 80cc/hr– Hb, WBC/DC, Plt, PT,APTT– F/C (282)– BUN, Cr, GOT, Na,K– PES– Pantoloc 1 amp iv st & Q12H

Laboratory data (day1)項目 檢驗數值 單位 參考值

WBC  3.3 X1000/ul 3.8‐10

Hb 9.7  gm/dl  11‐16

Differential count  *******

Segmented Neutro.                       75.4  %  37‐75

Lymphocyte  14.0 %  20‐55

Monocyte  7.6 %  4‐10

Eosinophil  2.7  %  0‐5

Basophil  0.43 %  0‐2

Platelet 148 x1000 140‐450

項目 檢驗數值

單位 參考值

PT 11.3 second 9.4‐12.5

Normal control 10.2 second

INR 1.11 Ratio 0.8‐1.2

APTT 28.5 second 28.6‐38.6

項目 檢驗數值

單位 參考值

GOT(AST)  36 U/L  5‐35BUN  23  mg/dL 8‐20Creatinine  1.0 mg/dL 0.5‐1.3Na  140 meq/L  133‐145K  4.2  meq/L  3.3‐5.1eGFR  71.36 

Hb: 1/19 12.23/20 9.3

Panendoscopy (day2)

• Stomach: active oozing lesion– APC (sclerotherapy) failedHemoclip failedHistoacryl (glue)success ! 

• Impression:  active bleeding in the fundusa varix bleeding        antrum ulcers

ER course

• day2 14:43– 做完胃鏡後,解兩次大

便(黃色)– No SOB– OPD medication: BokeyDC

– Hb: 9.78.9

• day2 22:00– No tarry stool– Vital sign:36.1/51/20, BP: 198/88

– f/u Hb cm– NTG 1# sl

Transfer to EC• day2 16:37

– NPO– IVF:D5S+KCl 10 mEq run 60cc/hr– Glypressin 2 amp st & 1 amp iv Q6H– Pantoloc 1 vial iv QD– F/S TIDAC+HS

• day3 14:24– Try water ,人仍虛弱

– No abdominal pain– 家屬主訴會頻尿

– T/P/R: 36.1/52/16BP: 173/78Hb:8.98.4

Check U/A, U/Cto r/o UTI

f/u Hb at 17:00預備血

• day3 23:20– 巧克力色大便一次

– 今天忘記喝水

– T/P/R:36.2/59/18– BP: 172/63Hb: 8.48.3

檢驗項目名稱

檢驗值 檢驗值單位

Sediment **********

RBC 1-2 /HPF

WBC 1-2 /HPF

Epithelial cell 0-1 /HPF

Cast Not Found /LPF

.cast-amount -

Crystal Not Found /HPF

.Cry-amount -

Bacteria -

Others Not Found

• day4 10:19– Yellowish stool– No dizziness/SOB

– Arrange abdomen echo(∵no liver cirrhosis hx )

Abdomen echo (day4)

Abdomen echo (day 4)• Diagnosis :                                                             

– Hepatic tumors, bilateral (metastatic tumors are highly suspected)      

– GB stones                                                               – Pancreatic tumor, head                                                  – Pancreatic cystic lesions, body                                         – Ascites

Abdomen CT (day4) Abdomen CT• Pancreatic tumor with liver metastasis

Tentative stanging :T4N0M1– Infiltrative hypodense mass at pancreatic head, the maximal diameter 

is about 2.8cm. It caused main pancreatic duct dilatation and cystic structures at pancreatic body.            

– The tumor encasing the common hepatic artery and invades the central SMV and main portal vein.   

– No obvious discrete regional lymphadenopathy identified.       

• Gallstones                                                           • Minimal right pleural effusion

day4 3個月前

• day4 18:00– Admission– Dx: pancreatic head tumor, GV bleeding, DM, HTN

– IVF:D5S/T5 + RI 8U run 80cc.hr

– Diet:NPO除水

– F/S:BIDAC– Pantoloc 1 vial QD– Glypressin 1 amp Q6H

• day5– Try liquid diet– IV on lock– DC Glypressin– Check tumor marker

檢驗項目名稱

檢驗值 檢驗值單位 最小參考值

AFP 1.03 ng/mL 0-7

CEA 76.26 ng/mL 0-5

CA 19-9 188790 U/mL 0-27

U/C:Colony count : 46000 Enterococcus spp.

AM GM1* P TEI VA S S S S S

Tentative diagnosis• Pancreatic tumor with liver metastasis, T4N0M1• Gastric varices• Gastric ulcer• Gallstones                                                           

Hospital course• Hb: 8.39• 拒biopsy• DNR全拒

• Supportive treatment– Pantoloc 1# QD

• Discharge on day7

Discussion

Management of acute variceal bleedingPrimary and secondary prophylaxis in varices

hemorrhage 

Reference1. Treatment of acute variceal bleeding

Digestive and Liver Disease 40 (2008) 328–336

2. Left‐Sided Portal HypertensionDig Dis Sci (2007) 52:1141–1149

3. Primary and secondary prophylaxis of gastric variceal bleedingF1000 Medicine Reports 2010, 2:26 (doi:10.3410/M2‐26)

4.Prediction of variceal hemorrhage in patients with cirrhosisuptodate

5. Primary and pre‐primary prophylaxis against varicealhemorrhage in patients with cirrhosis

uptodate

Introduction• Bleeding in portal hypertension 

– gastro‐oesophageal varices (GOV, 65–70%)isolated gastric varices (IGV, 10–15%)

– Other cause: portal hypertensive gastropathy (PHG), Mallory Weiss lesions and peptic ulcer bleeding

• Clinical challenge due to high mortality– Six weeks mortality decreased from 40% 15%– Mortality : 

• closely related to failure to control the initial bleeding • early re‐bleeding (30–40% within the first 5 days)

Introduction• Pharmacologic (somatostatin/vasopressin analogous) Tx:

– decrease portal inflow and mediate splanchnicvasoconstriction

• Emergent endoscopic Tx:– requires skilled endoscopists– adverse events in 10–20% of patients

Introduction

• EV vs. GV– Initial procedures and treatment : identical

– GV: no response to  pharmacologic treatment • different treatment from EV• Isolated gastric varices (IGV) consider left‐sided portal hypertension (LSPH)

Pathophysiology• Portal hypertension: gradient > 5mmHg

– 8‐10 mmHg: esophageal & gastric varices– >12 mmHg: variceal bleeding

• Gastroesophageal varices– 50% in cirrhosis– Esophageal varices

• common in cirrhosis• new varices : 5% within 1 year 28% of patients within 3 years• Small to large varices: 8%  per year• strongest predictor :HVPG > 10 mmHg

– Gastric varices• less frequent than esophageal varices

Classification of gastric varices

75% 21%

1-2% 4%

Classification of portal hypertensionPre‐hepatic

Portal vein thrombosis

Splenic vein thrombosis

Post‐hepatic

Budd‐Chiari syndrome

Right sided heart failure

Constrictive pericarditis

High‐flow portal hypertension

Hepatic artery‐portal vein fistula

Splenic AV fistula

Massive splenomegaly

Intra‐hepaticPresinusoidal Sinusoidal              Postsinusoidal

Schistosomiasis Alcoholic cirrhosis Alcoholic cirrhosis

Primary biliarycirrhosis

Storage diseases Veno‐occlusive disease

Sarcoidosis Hemochromatosis

Myeloproliferativedisease

Wilson’s disease

Gaucher’s disease

Congenital hepatic fibrosis

Arsenic toxicity

Etiology of LSPH• Splenic vein thrombosis (SVT)

– normal liver function & unexplained splenomegaly– curable by splenectomy in variceal bleeding– Strong association with pancreatic disorders

• acute and chronic pancreatitis and pancreas neoplasms– 35% : tumors, 17%: pancreatitis 

• Others: compression of the splenic vein – organs, edema, enlarged LN, and splenic artery aneurysm

Diagnosis• Gold standard: esophagogastroduodenoscopy (EGD)

• Definition:  bleeding from EV/GV at the time of endoscopy– Absence of active bleeding (up to 50% ) either a “white nipple sign”

– GV (+): fresh blood in the fundus– Medium or large varices with no other potential bleedingsuggest varices as the source of haemorrhage.

Diagnosis• Endoscopy

– Endoscopic ultrasound: gastric varices /folds– Portal vein angiography or abdomen CT– Brium x‐rays : large esophageal varices / large gastric folds suggestive of gastric varices

– Capsule endoscopy

Management

Management• Resuscitation and correction of hypovolaemia

– Protect the airway prevent pulmonary aspirationincreased risk phenomena

– Pulse oximetry+ O2 supply+ suction– At least one large (14–18 gauge)IV– Volume expansion

• no specific evidence to support the type of plasma expanderI

– Transfusion• goal of transfusion: Hb8g/dL, HCt25 ‐30%• coagulopathy• Not to overtransfuse !! ‐‐ ↑ portal pressure and↑ risk of early rebleeding as well as pulmonary congestion

– NG  insertion : controversial• no document to improve survival or decrease complication rate

– In massive uncontrolled bleeding:  Sengstakentube

• high complication rate: aspiration pneumonia, necrosis of oesophageal mucosa and obstruction of airways

– Intubation • encephalopatic patients or uncontrolled severe bleeding

• Prevent and treat infection– Bacterial infections are frequent in cirrhosis 

• 20% at initial hospitalisation ,  50% later during the hospitalisation• UTI (12–29%) :GNB , E. coli or Klebsiella• SBP (7–23%):GNB, GPC and Staphylococcus

– Higher risk of variceal rebleeding

– Two meta‐analysis : short‐term Abx prophylaxisdecrease  9% mortality

Quinolone ±Amoxicillin /Clavulinic acid VS. placebo

Dose: 400 to 1000 mg daily

Duration: single dose up to 10 days

Prophylactic antibiotics                                           ※Mortality: relative risk reduction of 29% 

※ Incidence of bacterial infec ons : ↓ 58% 

Norfloxacin vs. ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049–56.

severe cirrhosis and bleeding

oral Norfloxacin(400 mg BID

33% bacterial infection

IV Ceftriaxone(1 g per day)

11%bacterial infectionP=0.03

All cirrhosis with UGIB Receive prophylactic tantibiotics

Quinolones or IV cephalosporin’sfor 5–7 days

Avoid aminoglycoside for renal toxicity 

• Monitor renal function– Keep the urine output > 40 ml/hr– Avoid nephrotoxic drugs:  aminoglycosids and NSAID– Renal failure : variceal bleeding and hypovolaemic shock dialysis

– Tense ascites: massive paracentesis albumin replacement

Medical treatment of variceal bleeding in cirrhosis

• Goal: reduce portal pressure– Higher portal pressure>20 mmHg : less favourableprognosis

• early rebleeding (within the 1st week of admission) • failure to control bleeding (83% vs. 29%)• higher 1‐year mortality (64% vs. 20%) 

• Splanchnic vasoconstrictors – vasopressin and analogues– somatostatin and analogues

• Venodilators– Nitrates  

• systemic hypotensive effect decrease in portal pressure more related to hypotension

• Vasopressin and analogues (Terlipressin) – Terlipressin: long‐acting synthetic vasopressin anaogue, less CV side effects compared to vasopressin

• Vasopressin: cardiac/ peripheral ischemia, arrythmia, HTN,bowelischemia

– ↓portal pressure with approximately 20% a er a single dose

– A meta‐analysis of 7 published RCT• Terlipressin : more effective than placebo for control of varicealbleeding

– Control acute variceal bleeding is 75–80% • RR: 0.66, 95% CI: 0.49–0.88

– The only vasoactive treatment to reduce mortality– Benefit effect on renal function

• Somatostatin and analogues (octreotide)– reduces portal pressure (HVPG) of approximately 17% without affecting systemic hemodynamics

– the best effect : bolus injections• Continuous infusion :no effect on HVPG and the effect seem to vanish during repeated bolus injections

– control of bleeding and borderline significance in rebleeding

– no effect on decrease of mortality rate

Medical treatment• Terlipressin first line treatment

– decrease mortality!!

• Somatostatin and its analogues– equal effect– used if terlipressin is not administered

• Terlipressin and somatostatin or analogues given in combination never been evaluated

• Recombinant factor VIIa– Coagulopathy may progress during bleeding– All other treatments have failed rescue therapy

2 RCT additive to 

endoscopic and vasoactive therapy

no effect

control  acute bleeding

rebleedingrate

mortality

Effective

Child‐Pugh score of ≥ 9

significant decrease in 42‐day mortality

reduce rebleeding rate in the period day 5–42

1. Recombinant factor VIIa for upper gastrointestinal bleeding n patients with cirrhosis: a randomized, double-blind trial. Gastroenterology 2004;127:1123–30

2. Recombinant factor VIIa (rFVIIa) for active variceal bleeding in patients with advanced cirrhosis: a multi-center randomiseddouble-blind placebo-controlled trial. Hepatology 2008 (in press)

Endoscopic therapy 

• Diagnostic endoscopy ASAP– Clinical significant bleeding  :within 12 h– A longer delay in minor bleeding which response completely to vasoconstrictors. : within 24 h

Endoscopic therapy• Sclerotherapy

– Control acute bleeding and ↓42‐day mortality, – Prevent variceal rebleeding compared to medical therapy with vasopressin or balloon tamponade

• Control acute bleeding (OR 8.5) , rebleeding during first 2 weeks hospitalisation (OR 0.36 ) ,mortality (OR 0.57)

– Skilled:  aspiration  pneumonia, infections, ulcers with bleeding and after long ‐term treatment oesophagealstenosis

Endoscopic therapy• Banding ligation

– Superior to sclerotherapy• long‐term prevention of variceal bleeding • Fewer complications

– Emergent sclerotherapy VS. emergent banding • Severe bleeding ligation is difficfult• Initial endoscopic therapy sclerotherapy

• A randomized controlled trial comparing ligation and sclerotherapy as emergency endoscopic treatment added to somatostatin in acute variceal bleeding. J Hepatol 2006;45:560–7.

• Endoscopic treatment of bleeding esophageal varices. Endoscopy 2007;39:373.• Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal 

varices. Hepatology 1997;25:1101–4

Combined treatment

Synergic effect

endoscopic therapy        80–85%  control 

bleeding

vasoactive drugs            80‐85% control 

bleeding

Meta‐analysis :                               8 studies with 939 

patients 

beneficial effect on control ofbleedingOR 1.12 (1.02–1.23)

beneficial effect  on control of 5‐day bleeding  risk                                                   

OR 1.28 (1.18–1.39)

no significant effect on mortality

TIPS

• rescue intervention when other therapies have failed

Management of gastric varices

Gastric varices

• Bleed less frequent than EV  

• Greater bleeding intensity and transfusion requirements higher mortality once bleeding has occurred

• Lack of RCT about treatments in GV bleeding – Endoscopeic sclerothrapy or ligation  difficult in  isolated fundic varices (IGV1)

Gastric varices• Treat with tissue adhesives

• A prospective, randomized trial of butyl cyanoacrylate injection versus band ligation in the management of bleeding gastric varices. Hepatology 2001;33:1060–4

• A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundicvarices. Am J Gastroenterol 2002;97:1010–5.

60 patientsprospective, randonmised

N‐butyl‐2‐cyanoacrylat

e glueligation

- Significant higher hemostasis- Reduced rebleeding rates- No mortality difference

17 patients  RCT

Cyanoacrylateglue

Obliteration 100%

Sclerotherapy

Obliteration 44%

-Better initial hemostasis- Lower rebleedingrate-Complication (thromboembolic): pulmonary emboli, stroke, coronary embolism

Gastric varices• Thrombin

– Not carry the risk of embolization and damage to equipment  compared to  cyanoacrylate

– Control GV bleeding :92%  hemostasis rate and no episodes of rebleedingThe use of thrombin injections in the management of bleeding gastric varices: a single‐center experience. Gastrointest

Endosc 2008, 68:877‐82

– Controlled trials comparing thrombin with other gents are required

Gastric varices• TIPS

– Used extensively in EV bleeding – Limited data on TIPS for GV: less common– In a study of 28 patients with actively bleeding fundal varices Gastroenterology 1998;114:981–7

• 96% initial haemostasis and 28% rebleeding rate 

• Balloon tamponade– efficient as a bridge to a more definite treatment

Isolated gastric varices• IGV1  

– exception and frequently result from isolated splenic vein thromboses.

– the treatment of choice : splenectomy Prognosis

• Bleeding risk factors: GV similar to EV– Location of varics– Size of varices– Clinical features– Appearance of varices– Variceal pressure

• Location of varics– EV:  gastroesophageal junction   thinnest layer of supporting tissue– GV: IGV> GOV2>GOV1>IGV2

• Size of varices– EV

• F1: Small, straight varices• F2: Enlarged, tortuous varices ,<1/3 of the lumen• F3:Large, coil‐shaped varices , >1/3 of the lumen

– GV• Large: >10mm• Medium:>5mm• Small:<5mm

• Appearance of varices– red appearance, or "red signs“

• Clinical features– Child score– Hx of previous variceal bleeding

– early rebleeding : greatest immediately after cessation of active hemorrhage (50 % rebleeding within 48 hours) and subsides over time

• Variceal pressure– 87 patients with cirrhosis and large EV , never varicealbleeding were followed for 12 months

Variceal pressure is a factor predicting the risk of a first variceal bleeding: a prospective cohort study in cirrhotic patients.           Hepatology 1998; 27:15

Variceal pressure (mmHg) Number of bleeding (%)

≤13  0/25 ( 0 %)

13‐14 1/11  ( 9 %)

14‐15 2/12  (17 %)

15‐16 7/14  (50 %)

>16 18/25 (72 %)

Cut point: 15.2mmHgsignificantly improved the predictive value of this classification

Risk factors Early rebleeding(<6 weeks )

Late rebleeding(>6 weeks)

Age >60 years O x

Severity of initial bleeding (hypotension, severe anemia)

O x

Renal failure O x

Severity of liver failure O O

Ascites O O

Hepatoma unknown O

Active alcoholism X O

Active bleeding on endoscopy O X

Increasing varix size O O

Red signs O unknown

Platelet clot on varix O unknown

Portal pressures unclear X

rChild class A Child class B Child class C

F1 F2 F3 F1 F2 F3 F1 F2 F3

-- 6 10 15 10 16 26 20 30 42

+ 8 12 19 15 23 33 28 38 54

++ 12 16 24 20 30 42 36 48 64

+++ 16 23 34 28 40 52 44 60 76

Estimations are based upon one-year percentage probability of bleeding. F1, F2, F3 refer to size of the varix.

Adapted from: deFranchis R, N Engl J Med 1988; 319:983.

Prophylaxis

Pre‐primary prophylaxis• Prevent the development of varices in patients with portal hypertension– Treat underlying liver disease– Non‐selevctive β‐blocker is not recommended– Receive routine screening endoscopies

Randomised, 213  patientsportal hypertension without EV

Primary end point(follow 55 m/odevelope varices or variceal bleeding)

Secondary end point(developof ascites, need for liver transplantation, or death)

non‐selevctive β‐blocker :timolol

39%  (42 of 108) No difference

placebo 40%  (42 of 105)

P=0.89

Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353:2254

Primary prophylaxis of EV• Goal: prevention of a first variceal hemorrhage in a patient with varices– B‐blocker and endoscopic EVL

Primary prophylaxis B‐blocker EVL

Variceal hemorrhage higher lower

Mortality no difference

Procedure complication x O

Decrease ascitesdevelopment, SBP

Primary prophylaxis of EV• American Association for the Study of Liver Diseases (AASLD) 

guidelines: non‐selective B‐blocker, EVL

Small varices with red signs or Child B or C cirrhosis 

NonselectiveB‐blocker

try EVL If not tolerate B‐blocker

Medium or large varices

Tolerance , risk of procedure

Nonselective B‐blocker or EVL

EVL is more effective in large varicesEndoscopic band ligation versus pharmacological therapy for variceal bleeding in cirrhosis: a meta-analysis. Can J Gastroenterol 2011; 25:147

Primary prophylaxis of EV• Child A cirrhosis with small varices without red signs 

– No primary prophylaxis– Routine upper endoscopy  the development of red signs or for variceal enlargement

• Approach not recommended:– Nitrates (alone or in combination with B‐blocker)

• variable results about whether nitrates decrease hemorrhage risk

– Shunt therapy– Sclerotherapy

Primary prophylaxis of GV• Based on guidelines for managing EV

– No studies about pharmacologic or endoscopic therapy for primary prophylaxis of  GV

• Likely to bleed: large GV with red color signs, especially with advanced liver disease ( Child C)treated with non‐selective b ‐blockers to prevent varicealhemorrhage

• Endoscopic treatment or TIPS – not currently recommended for primary prophylaxis of gastric varices

Secondary prophylaxis• Goal: prevent rebleeding

– 60% :  rebleed within 2 years with a mortality rate of 33%

• Current recommendation: – EV: EVL and nonselective B‐blocker 

• 2 prospective trials : combination of EVBL with medical therapy (nadolol) may be superior to EVBL alone

– GV: Tissue adhesives : the treatment of choice• lower complication rate, comparable hemostasis and survival rates, and lower cost

• TIPS : not recommended– lower rebleeding rates compared to medical/endoscopic therapy

– higher costs and incidence of hepatic encephalopathy

Back to our patient

Back to our patient• Non‐cirrhotic GV

– Etiology

• Isolated fundus varices ( IGV1)– Vasoactive agent:  glypressin– Endoscopic treatment: glue> sclerotherapy, ligation

• Prophylatic Abx– UTI?  No pyuria, Enterococcus with colony 46000

• Rebleeding risk– Fundus + red sign , unknown size and pressure

• Secondary prophylaxis– Tissue adhesives: histoacryl (N‐butyl‐2‐cyanoacrylate) Injection

Thanks for your attention! 

Secondary prophylaxis of GVLo et al. prospective RCT

Endoscopy 2007, 39:679‐85Tissue adhesives (cyanoacrylate glue), N=37

TIPS, N=35

Survival, Complication rates No difference

Rebleeding rate Significantly higher: 38% 11%

Mahadeva et al, retrospectiveAm J Gastroenterol 2003, 98:2688‐93.

Tissue adhesives (cyanoacrylate glue)

TIPS

Initial hemostasis No difference

Rebleeding rate Higher: 35% 20%  (expensive!!)

Procaccini et al, retrospectiveGastrointest Endosc 2009, 70:881‐7.

Tissue adhesives (cyanoacrylate glue),N=61

TIPS, N=44

Rebleeding rate, Mortality No difference

Morbidity requiring hospitalization Lower Higher

Incidence of encephalopathy 1 Higher :11