management of hospitalized patients with cirrhosis
TRANSCRIPT
10/26/2015
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Management of Hospitalized Patients with
Cirrhosis
Bilal Hameed, MD
Division of Transplant Hepatology
University of California, San Francisco
I have no financial relationships to disclose within the past 12 months
relevant to my presentation
My presentation does not include discussion of off-label or investigational
use
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Outline
Complications of cirrhosis 1. Portal hypertension related variceal bleed
2. Ascites, hyponatremia and hydrothorax
3. Hepatic encephalopathy
4. Renal failure and HRS
Infections in cirrhosis
Liver transplantation
Compensatedcirrhosis
Decompensatedcirrhosis
Death
Natural History of Cirrhosis
Development of complications:
Variceal hemorrhage Ascites Encephalopathy Jaundice
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Question
Most common decompensation in patient with cirrhosis?
1. Variceal bleed.
2. Hepatic encephalopathy.
3. Ascites.
4. HCC.
5. Jaundice.
Ascites (58%)JaundiceEncephalopathyGI hemorrhage
Probability of developing event
0
20
60
80
100
0 60
40
20 40 80 100 120 140 160
MonthsGines et. al., Hepatology 1987.
Complications in Compensated Cirrhosis
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6040 80 100 120 140 1600
40
60
80
20
200
100
Months
Probability of survival
All patients with cirrhosis
Decompensated cirrhosis
180
Median survival~ 9 years
Median survival~ 1.6 years
Gines et. al., Hepatology 1987.
Decompensation Shortens Survival
Esophageal Varices
Seen in 50% patients with cirrhosis
10-15% of all GI bleeds (~ 40,000 patients)
$1.2 billion in health care expenditure
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Small varicesSmall varices Large varicesLarge varicesNo varicesNo varices
7-8%/year7-8%/year 7-8%/year7-8%/year
Merli et al. J Hepatol 2003;38:266Merli et al. J Hepatol 2003;38:266
Varices Increase in Diameter Progressively
%Patients without bleeding
%Patients without bleeding
100100
5050
2525
00
00 1212 2424
7575
36361212 2424 3636
Large Varices * *
p<0.01 *p<0.01 *
2-year probability of first bleed: Small varices: 7% Large varices: 30%
2-year probability of first bleed: Small varices: 7% Large varices: 30%
Time (months)Time (months)
No Varices
Small Varices
*Merli et al., Hepatol 2003,
**Conn et al., Hepatology 1991
*Merli et al., Hepatol 2003,
**Conn et al., Hepatology 1991
Large Varices Are More Likely To Rupture
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What is the Risk of Mortality with Variceal Bleed?
1980 2013
2 months mortality 40%
6 weeks mortality 20%
•Pharmacotherapy•Endoscopic innovations•IR Procedures•Better ICU care
Better Bleeding Control Resulted in Decrease Mortality
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Case Presentation
60-year-old female with NASH cirrhosis is brought to the ER because of melena. No prior endoscopy. Hgb is 8 (baseline 11).
What is the best pharmacologic treatment option?
1. IV PPI
2. IV PPI and IV octreotide
3. PO PPI, octreotide and antibiotics
4. IV PPI, octreotide and antibiotics
Case Presentation
60-year-old female with NASH cirrhosis is brought to the ER because of melena. No prior endoscopy. Hgb is 8 (baseline 11).
What is the best pharmacologic treatment option?
1. IV PPI
2. IV PPI and IV octreotide
3. PO PPI, octreotide and antibiotics
4. IV PPI, octreotide and antibiotics
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Role of Endoscopy
40-50% have non variceal source of bleeding like PUD, esophagitis, MW tear etc.
Dig Dis. 2005;23:11-7.
Case Presentation
50-year-old male with HCV related cirrhosis is brought to the ER because of melena and hypotension (SBP 80 mmHg). What is the first priority in the management of this patient?
Emergent upper endoscopy.
Start antibiotics for SBP prophylaxis.
Transfuse blood.
Venous access and hemodynamic stability.
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Case Presentation
50-year-old male with HCV related cirrhosis is brought to the ER because of melena and hypotension (SBP 80 mmHg). What is the first priority in the management of this patient?
Emergent upper endoscopy.
Start antibiotics for SBP prophylaxis.
Transfuse blood.
Venous access and hemodynamic stability.
Treatment of Acute Variceal Hemorrhage
General Management: IV access and fluid resuscitation
Airway protection
Antibiotic prophylaxis
Correct coagulopathy
Specific therapy: Pharmacological therapy
Early endoscopic therapy: band ligation
Shunt therapy: TIPS, surgical shunt
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Transfusion Strategy: Too Much is Bad!
921 pts (277 with cirrhosis)
Restrictive (Hgb <7) vs liberal transfusion (Hgb <9)
Liberal strategy had increase portal pressure and rebleeding (11% vs 22%)
Survival was improved with restrictive transfusions
Villanueva et al, NEJM 2013
Control Antibiotic Absolute rate(n=270) (n=264) difference
(95% CI)
Infection 45% 14% -32%(-42 to –23)
SBP / Bacteremia 27% 8% -18%(-26 to –11)
Death 24% 15% -9%(-15 to –3)
Control Antibiotic Absolute rate(n=270) (n=264) difference
(95% CI)
Infection 45% 14% -32%(-42 to –23)
SBP / Bacteremia 27% 8% -18%(-26 to –11)
Death 24% 15% -9%(-15 to –3)
Bernard et al., Hepatology 1999; 29:1655Bernard et al., Hepatology 1999; 29:1655
Meta-analysis of 5 randomized trials
Prophylactic Antibiotics Improve Outcomes
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Hou M-C et al., Hepatology 2004Hou M-C et al., Hepatology 2004
Prophylactic antibiotics (n=59)Prophylactic antibiotics (n=59)
%free of
varicealhemorrhage
%free of
varicealhemorrhage
1.01.0
0.6
0.6
0.2
0.2
0.8
0.8
1100
No antibiotics (n=61)No antibiotics (n=61)
0022 33 1212 3030Follow-up (months)Follow-up (months)
1818 2424
0.4
0.4
Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days
Ofloxacin 200 mg iv q12 hr for 2 days, then oral 200 bid for 5 days
Greatest benefit in first
7 days
Prophylactic Antibioics Reduce Probability of Recurrent Variceal
Hemorrhage
Pharmacological Treatment for Acute Variceal Bleed
Somatostatin Variable results in meta-analysis
Octreotide
Vasopressin
Terlipressin (Not available in US) Vasopressin analogue
Improve survival in some studies
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Pharmacologic therapy
Parameter Vasopressin Octreotide
Dose 20 U bolus; 0.4-0.6 U/min IV
50 bolus; 50 /hr IV
Hemostasis ~ 50% > 80%
Rebleed ~ 50% 14-30%
Complications 32-64% 0-15%
Mortality 5% 0
Gastroenterology 1995;109:1289-94 Aliment Pharmacol Ther. 2004;20:S18-22 Dig Liver Dis. 2004;36:S93-100
Endoscopic Band Ligation
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Refractory Variceal Bleeding
Balloon tamponade
TIPS
Surgical shunt
Hepatic veinHepatic vein
Portal veinPortal veinSplenic veinSplenic vein
Superior mesenteric veinSuperior mesenteric vein
TIPSTIPS
Transjugular Intrahepatic Portosystemic Shunt
1. Second rebleed for esophageal varices
2. First rebleed for gastric varices
3. Rebleed on combination endoscopic plus pharmacologic therapy (10-20%)
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Portal Hypertensive Bleed
Gastric Varices Portal HTN Gastropathy Typical GAVE “watermelon stomach
Case 56 yr with acute variceal bleed (1st episode)
Bleeding controlled with band ligation
No bleeding for 5 days
Child score 10. MELD 15 MAP 90 mmHg
Which is the best discharge regimen?
1) Beta blockers and nitrates
2) Serial ligation alone
3) Ligation and beta blockers
4) TIPS
5) Portacaval shunt
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Case 56 yr with acute variceal bleed (1st episode)
Bleeding controlled with band ligation
No bleeding for 5 days
Child score 10. MELD 15 MAP 90 mmHg
Which is the best discharge regimen?
1) Beta blockers and nitrates
2) Serial ligation alone
3) Ligation and beta blockers
4) TIPS
5) Portacaval shunt
(19 trials)(19 trials)(26 trials)(26 trials) (54 trials)(54 trials)
%%
RebleedingRebleeding
8080
6060
4040
2020
00UntreatedUntreated -
blockers-
blockersSclero-therapySclero-therapy
(18 trials)(18 trials)
LigationLigation
(6 trials)(6 trials)
HVPG-Responder
s*
HVPG-Responder
s*(6 trials)(6 trials)
-blockers+ ISMN
-blockers+ ISMN
(2 trials)(2 trials)
Ligation+
-blockers
Ligation+
-blockers
Bosch and García-Pagán, Lancet 2003; 361:952Bosch and García-Pagán, Lancet 2003; 361:952
* HVPG <12 mmHg or >20% from
baseline
* HVPG <12 mmHg or >20% from
baseline
Lowest Rebleeding Rates are Obtained in HVPG Responders and With Ligation + -Blockers
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Acute Variceal BleedKey Points
Ascites
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Causes of Ascites
Cause ProportionCirrhosis 80%
Malignancy 10%
Heart Failure 4%
Nephrotic Syndrome 2%
Tuberculosis 2%
Pancreatitis 1%
Others (Budd Chiari) 1%
Case
47 yr old male with hepatitis C cirrhosis now presented with new onset abdominal distention and leg swelling.
Ultrasound showed large ascites. No evidence of portal vein thrombosis.
INR 2.2
530
62
50 667.0
140
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Which Statement is correct?
1. Need correction of INR before paracentesis.
2. No need to send cell count as no abdominal pain and fever.
3. SAAG of > 1.1 is only seen in portal hypertension.
4. Direct inoculation into blood culture bottles at the bedside improves yield.
Which Statement is correct?
1. Need correction of INR before paracentesis.
2. No need to send cell count as no abdominal pain and fever.
3. SAAG of > 1.1 is only seen in portal hypertension.
4. Direct inoculation into blood culture bottles at the bedside improves yield.
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SAAG
Serum-ascites albumin gradient SAAG = serum albumin – ascites albumin
SAAG ≥1.1 g/dL is 97% accurate at diagnosing ascites due to portal hypertension
High SAAG and high total protein (>2.5 g/dL) suggests cardiac cause
Probability of Survival is Poor After Developing Ascites
56% 5 year survival
Planas et al. Clin Gastroenterol Hepatol. 2006
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When to Perform Paracentesis
Rule out SBP
Any new onset ascites
Any admission to hospital
Worsening of controlled ascites
Any change in clinical status
-- Encephalopathy
-- Unexplained renal failure
Ascitic Fluid Analysis
Runyon, Hepatology 2004
Routine Optional(Suspicion for Infection)
Unusual
Cell count & differential
Culture (bedside) AFB
Albumin Glucose Bilirubin
Total Protein LDH Triglyceride
Amylase Cytology
Gram stain
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First-Line Therapy
Tense ascites
Paracentesis
Sodium restriction(<2 Gm/24 Hrs)and diuretics*
Non-tense ascites*Diuretics: Spironolactone 100 mg/day,furosemide 40 mg/day or bumetanide1 mg/day; uptitrate stepwise to spironolactone 400 mg/day, furosemide160 mg/day or bumetanide 4 mg/day astolerated
RefractoryAscites 10 %
Second-Line Therapy
• Repeated large volume paracentesis
• TIPS
• Liver Transplantation
Management of Ascites
Adapted from Runyon BA. Hepatology. 2009; 49:2087-2107.
Treatment of Refractory Ascites
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0
2
4
6
8
10
12
14
16
18
Bleeding Ascites Pre-opDecompression
71%
25%4%
Courtesy Dr.Jeanne M. LaBerge
TIPS Indications:UCSF
Treatment: Serial LVP
Colloid replacement is important
Patients receiving albumin had less hemodynamic deterioration, renal failure and hyponatremia
Recommendation to administer 6-8 gm albumin per L of ascites removed if more than 5 L removed
Recent meta-analysis of 17 studies have shown improved survival in the albumin group
Bernardi M, Carceni P et al. Hepatology 2012Gines et al, Gastro 1988
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Routine prophylactic use offresh frozen plasma or platelets before
paracentesis? Not recommended
Complications were reported in only about 1% of patients
Bleeding conditions occur in less than 1 per 1,000 patients who require paracentesis
Coagulopathy should preclude paracentesis only when there is clinically evident hyperfibrinolysisor DIC
Pache I et al. Aliment Pharmacol Ther 2005.Caldwell SH et al. Hepatology 2006.
Ascitic Fluid Analysis: cell count
Normal ascites
Total WBC upper limit 500 cells/mm3
Total count can concentrate with diuresis, but not PMN count
PMNs normally account for 25-30%
SBP definition PMNs >250 cells/mm3
Culture: Direct inoculation into blood culture bottles at the bedside to improve yield
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SBP Start broad spectrum antibiotics immediately
Community acquired SBP- Causes: Gram negative (E.Coli)
- 3rd generation cephalosporin (cefotaxime for 5-7 days)
Hospital acquired SBP- High risk of ESBL E.coli
Treatment Failure- Secondary bacterial peritonitis
- Resistant organism
Treatment Trials for SBP
Study N Results p HospitalMortality
Cefotaxime vs ampicillin/tobramycin
73 Cure 85% vs 56% <0.02 33% vs 43%
Cefotaxime5 vs 10 days
100 Cure 93% vs 91%Recurrence 12% vs 13%
NS 33% vs 43%
Oral ofloxacinvs cefotaxime
123 Resolution 84% vs 85%
NS 19% vs 19%
Cefotaximewith or without Albumin
126 Resolution 98% vs 94%
Renal failure10 vs 33%
NS
0.002
10% vs 29%
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Probability of SBP recurrence
Months0
1.0
.8
.4
.2
.6
3 6 12 24 360
Recurrence of Spontaneous Bacterial Peritonitis is Common
Titó et al., Hepatology 1988; 8:27
70%
Case
47 yr old male with hepatitis C cirrhosis with ascites. He is on lasix and aldactone which was recently increased.
Exam showed large ascites.
Now fatigue and worsening encephalopathy.
116
5.0 20 1.00103
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Which statement is NOT True
Need to stop diuretics.
Start hypertonic saline.
Fluid restriction.
Associated with increase mortality.
Potential Consequences of Hyponatremia
Hepatic encephalopathy
Reduced quality of life
Neurologic consequences after liver transplantation
Central Pontine Myelinolysis
High incidence in patients with Na<127 prior to OLT
Associated with rapid correction of sodium
May not be reversible
Increased risk of hepatorenal syndrome and death
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Types of Hyponatremia in Cirrhosis
HypovolemicHyponatremia
HypervolemicHyponatremia
Definition Na<130 in setting of intense sodium loss and contraction of intravascular volume
Na<130 in setting of solute free water retention and expansion of ECF volume
Clinical Findings
Develops in a few daysSigns of dehydrationNo ascites/edemaEncephalopathy present
May be transientAscites/edema presentEncephalopathy variable
Causes Over diuresisSodium lossDiarrhea
Excess of solute-free water(spontaneous, fluid induced, drug induced, infections)
Management Stop diureticsTreat diarrheaGive sodium cautiously
Reduce fluid intake: free water restriction
Increase free-water excretion
Types of Hyponatremia in Cirrhosis
HypovolemicHyponatremia
HypervolemicHyponatremia
Definition Na<130 in setting of intense sodium loss and contraction of intravascular volume
Na<130 in setting of solute free water retention and expansion of ECF volume
Clinical Findings
Develops in a few daysSigns of dehydrationNo ascites/edemaEncephalopathy present
May be transientAscites/edema presentEncephalopathy variable
Causes Over diuresisSodium lossDiarrhea
Excess of solute-free water(spontaneous, fluid induced, drug induced, infections)
Management Stop diureticsTreat diarrheaIV albuminGive sodium cautiously
Reduce fluid intake: free water restriction
Increase free-water excretion
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Conclusions
Ascites is very common in cirrhosis Should be tapped whenever new, different, or
admitted to the hospital
Low index of suspicion for SBP
Need IV albumin for LVP
Hyponatremia should be managed according to overall volume status of the patient
Case
47 yr old male with NASH cirrhosis. History of hepatic hydrothorax. Now with worsening SOB.
He had 2 thoracentesis last month.
Best long term treatment for him?
1. Chest tube placement
2. Pleurodesis
3. TIPS procedure
4. Liver transplant
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Hepatic Hydrothorax
Occurs in 5-10% with decompensated cirrhosis
Passage of ascites through diaphragmatic defect
Risk of spontaneous bacterial pleuritis
Mainstay is control of ascites
Chest tube is not indicated
Hepatic Hydrothorax:Treatment Options
Repeated thoracentesis
TIPS (50% patient may not be candidate)
VATS and diaphragmatic repair (low success rate and high mortality)
Denver shunt (pleuro-venous shunt)
PleurX Catheter
Liver Transplantation
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Hepatic Encephalopathy
Case
47 yr old male with hepatitis C cirrhosis. Wife brought him to ER with 3rd episode of hepatic encephalopathy.
On exam he is sleepy and has asterixis.
What is not needed in the work up?
1. Infectious work up
2. Rectal exam/melena
3. Diagnostic paracentesis
4. Ammonia level
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Prevalence of Hepatic Encephalopathy
Two forms of HE are recognized: Overt and Minimalbased on the nature and severity of clinical manifestations
Overt hepatic encephalopathy (OHE) occurs in:
‒ 30 to 45% of cirrhotic patients
‒ 10 to 50% of patients with TIPS
Poor Survival
42% at 1 year
23% at 3 years
Mullen KD et al. Semin Liver Dis. 2007. Poordad FF. Aliment Pharmacol Ther 2006.Bustamante J et al. J Hepatol. 1999.
Blood Ammonia and Diagnosis of HE
Accuracy is Technique-Dependant
Efficient venous draw, rapid transport on ice to reliable lab, quick analysis, pH controlled
Not Specific
Elevated in TPN, GI hemorrhage, intense muscular activity, and urosepsis
Limited Reliability
Overt HE is not always accompanied by a very high ammonia
Not a Guide to Treatment
Not a useful clinical endpoint for HE treatment in practice
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Case
A 63-year-old woman with NASH cirrhosis in the ER.
She had slurring of her speech and was “confused,” according to her husband that worsened overnight
It was difficult for her to maintain her balance and fell while in the bathroom and hit her head
First step in management is?
1. Blood cultures
2. Ultrasound
3. Head CT
4. Diagnostic paracentesis
Precipitating Factors Involved in Overt HE
GI hemorrhageConstipationPortosystemic shuntDeterioration in liver function
Psychoactive Medications
BenzodiazepinesNarcotics, sedatives
Dietary proteinNoncompliance
Blei AT et al. Am J Gastroenterol. 2001;96:1968-1976. Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.
Infection ShockAnemiaSurgery
Renal/electrolyte disturbances:Renal failure Metabolic alkalosis HypovolemiaHypokalemiaHyponatremia
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HE Treatment Goals
Blei AT et al. Am J Gastroenterol. 2001.
Provide supportive care
Identify and remove precipitating factors
Reduce nitrogenous load from gut
Assess need for long-term therapy
1
2
3
4
Reduction of nitrogenous load from gut Bowel cleansing
Non-absorbable disaccharides (lactulose)
Antibiotics (rifaximin, metronidazole)*
Agents that bind NH3 in the gut Na benzoate Na phenylacetate Na hydroxybutyrate Glycerol phenyl butyrate
Drugs that affect neurotransmission (flumazenil)
Manipulation of splanchnic circulation (occlusion of portal-systemic collaterals) Occlude TIPS shunt if present
* Neomycin (historical interest).Adapted from Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976.
Treatment Options for HE
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Current Therapy Options for HE
Drug Name Drug Class Indication
LactulosePoorly absorbed disaccharide
• Decrease blood ammoniaconcentration
• Prevention and treatment of portal-systemic encephalopathy
RifaximinNon-aminoglycoside semi-synthetic, nonsystemic antibiotic
Reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age.
NeomycinAminoglycoside antibiotic
Adjuvant therapy in hepatic coma
MetronidazoleSynthetic antiprotozoal and antibacterial agent
Not approved for HE
Vancomycin Aminoglycoside antibiotic
Not approved for HE
Adapted from http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM203247.pdf, accessed 02/17/11
• Mechanism of action:
– A non-absorbable dissacharide
– Bacterial flora metabolizes in the colon to lactic acid lowers the colonic pH
• Administered orally, by mouth or through a nasogastric tube or via retention enemas
• Start 25 mL every 1-2 hours until at least two soft or loose bowel movements. Subsequently, the dosing is titrated to 3-4 soft stools per day
• Monitor stool output and side effects
Lactulose
Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. Ferenci P. Semin Liver Dis. 2007;27(suppl 2):10-17.Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547.
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Bass NM. Semin Liver Dis. 2007.. Mullen KD et al. Semin Liver Dis. 2007.
• Minimally absorbed (<0.4%) oral antibiotic
• No clinical drug interactions reported
• No dosing adjustment required in patients with liver disease or renal insufficiency
• Approved for overt recurrent HE risk reduction in patients ≥18 years of age
Rifaximin
0
0.2
0.4
0.6
0.8
1
0 28 56 84 112 140 168
Rifaximin: Time to Breakthrough HE Episode (Primary Endpoint)
Rifaximin
Placebo
Pro
port
ion
With
out
HE
Bre
akth
roug
h
0.77
0.53
Days Post-Randomization
58% in risk of HE breakthrough (P<.0001)
Bass et al. N Engl J Med. 2010.
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Nutritional Management in HE
Importance of preserving muscle mass
Avoidance of protein restriction Protein generally well-tolerated at 1.0-1.5 g/kg/d
More vegetable, less animal sources
Branch-chain amino acids (BCAA): Many studies, analyses - remains controversial
HE Summary
HE is very common in the cirrhotic patient
Ammonia is not useful for clinical endpoint in HE treatment
Look for precipitating factors of HE
Minimize narcotics and sedatives
Lactulose and rifaximin are the main treatment options
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Renal Dysfunction in Cirrhosis
The Kidneys are also important?
Renal dysfunction is one of the most important risk factors for adverse outcomes in patients with cirrhosis
Found in 20% of cirrhotics admitted to the hospital
The average cirrhotic will experience ~2 episodes per year
Acute kidney injury (AKI) in cirrhosis is associated with:
7-fold increase in overall mortality
Fede, J Hep 2012. Martin-Llahi, Gastro 2011. Tsien, Gut 2013.
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Case
50 yr old female with hepatitis C cirrhosis complicated by ascites. He is on diuretics.
No new medications. Normal creatinine last week.
125
5 16 2.5
Case
What is the most likely etiology his AKI?
1. Hepatorenal syndrome (HRS).
2. Obstructive (post-renal).
3. Pre-renal azotemia.
4. ATN.
5. Cryoglobulinemia.
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Case
What is the most likely etiology his AKI?
1. Hepatorenal syndrome (HRS).
2. Obstructive (post-renal).
3. Pre-renal azotemia.
4. ATN.
5. Cryoglobulinemia.
Differential Diagnosis of Renal Dysfunction in Cirrhotics
Pre-renal azotemia Hepatorenal
syndrome
Intrinsic renal disease
Post-renal disease
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Intrinsic Renal DiseaseType Typical clinical setting
Acute tubular necrosis(ATN)
Hypotension, IV contrast, prolonged hepatorenal syndrome
Acute interstitial nephritis (AIN)
Beta-lactam antibiotics (Zosyn, Augmentin), cephalosporins(ceftriaxone), NSAIDs
IgA nephropathy* Cirrhosis, especially alcoholic
Membranous nephropathy* Hepatitis B / C
Membranoproliferativeglomerulonephritis (MPGN) / cryoglobulinemia*
Hepatitis B / C
* Renal biopsy is needed to make the diagnosis.
Pre-Renal Azotemia
The most common cause of AKI in cirrhosis
Diagnostic evaluation:
Urine studies (fractional excretion of sodium)
R/o obstruction
Management:
DiureticsDiuretics
Diarrhea (lactulose)Diarrhea
(lactulose)
Acute GI bleed
Acute GI bleed
LVP w/o albuminLVP w/o albumin
NSAIDs, ACE-I
NSAIDs, ACE-I
Common causes of
renal hypo-perfusion
in cirrhotics:
Poor PO
intake
Poor PO
intake
• IV hydration with IV albumin 1g/kg• Treat the underlying cause • Remove the offending agent
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Hepatorenal syndrome (HRS)
Functional pre-renal azotemia
85% have an identifying stressor
Tsien, Gut 2013. Arroyo, J Hep 2013.
Type 1 Type 2
Rapid (<2 weeks) Speed Slower course
2x baseline and>2.5 mg/dL
Creatinine >1.5 mg/dL
Typically SBP Associated with Refractory ascites
ReversibleResponse to
treatmentMay be reversible but usually recurs
Extremely poor (days-weeks)
Prognosis Poor (months)
Diagnostic Criteria of Hepatorenal Syndrome
International Ascites Club Guidelines.
• Presence of cirrhosis with ascites
• Serum creatinine >1.5 mg/dL
• No improvement in creatinine after:• Withdrawal of diuretics, and• 1 g/kg IV albumin per day (up to
100g/day max) for 2 days
• Absence of circulatory shock
• No recent administration of nephrotoxic medications
• Absence of intrinsic renal disease• Normal renal ultrasound• Bland urinalysis (no blood; <0.5 g/day
protein)
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HRS management: vasoconstrictors
Vasoconstrictors: V1 agonists
Vasopressin and its analogues (terlipressin)
A1-adrenergic agonists
Norepinephrine
Midodrine
Glucagon release inhibitor
Octreotide
Gines and Schrier, NEJM 2009
Management of Hepatorenal Syndrome
STEP 1
STEP 2
STEP 3
• IV Albumin 1g/kg per day x 2 days (max 100g/day)
• Treat precipitating factors
Manage what you can
• Midodrine 7.5 mg PO TID• Octreotide 100 mcg SQ TID
• Continue IV albumin 25-50 g/day)
Start vasoconstrictors
• Raise mean arterial pressure (MAP) by >15 mmHg
• Max midrodine 15 mg TID, octreotide 200 mcg TID
Titrate
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Key Points
Acute kidney injury is an important
prognostic marker in cirrhotics
50% risk of death in the first month
Causes can be categorized as:
Hepatorenal syndrome is diagnosed after an IV albumin challenge and ruling out other causes of AKI
Managed with midodrine, octreotide, and albumin
Pre-renal (most common)
Intrinsic renalPost-renal
Case
59 yr old male with HCV cirrhosis, complicated by ascites and HE. His meld score is 18.
Admitted to the ICU with hypotention and sepsis.
1. What is his mortality?
2. Most likely source of infection?
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Infections in Cirrhosis
Bacterial infections are the leading cause of mortality in cirrhosis
One third patients have at least one infection
Increase in MDR organisms (40% in some latest studies)
Fernandez J et al. Hepatology 2011; Arvaniti V et al. Gastroenterology 2010
Bacterial Infections in Cirrhosis
Site Percentage
SBP 30 %
UTI 25 %
Pneumonia 20 %
Soft Tissue infection 10 %
Sepsis 5 %
Other 10 %
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Infections: Hospitalized Cirrhotic patients
207 patients studied
Most first infections were HCA (71%), then nosocomial (15%)
Second infections were seen in 24%
30 day mortality: 23%
Bajaj J et al. Hepatology 2012
CA: community acquired (blue)HCA: hospital acquired (brown)Noso: nosocomial (green)
Septic Shock in cirrhotic patients
Retrospective, 635 pt’s with sepsis
Mortality 75%
Fungal infections seen in 10% patients
Septic shock but Culture negative: 25%
Arabi YM et al. Hepatology 2012
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Does Timing and choice of antibiotics makes a difference? Inappropriate initial empiric antimicrobial
therapy was administered in 25%
The median time to appropriate antimicrobial was 7.3 hours
In bacterial septic shock, a single rather than 2 or more appropriate antimicrobials was used in 73%
Arabi YM et al. Hepatology 2012
Timing of Antibiotics by onset of hypotension and mortality
Hours
Arabi YM et al. Hepatology 2012
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Key Points
Sepsis mortality is high in cirrhosis (60-80%)
Bacterial infections are the most common infections
Low threshold for starting the antibiotics
Increase in resistant organisms
Liver Transplantation
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Liver TransplantationTiming of Referral
Early referral is the key Complications of Cirrhosis (Child’s B or C) Ascites Portal hypertensive bleeding Hepatic encephalopathy Spontaneous bacterial peritonitis Synthetic function abnormalities
Waiting list priority is based on liver disease severity (=MELD), not waiting time
Deceased Donor Liver AllocationFebruary 2002 Changes:
Child-Turcotte-Pugh Score MELD Score
■ Ascites ▬ Creatinine
■ Encephalopathy ▬ Bilirubin
■ Bilirubin ▬ Protime INR
■ Protime INR
■ Albumin
MELD Score = 0.957 x Loge (creatinine mg/dL) + 0.378 x Loge(bilirubin mg.dL) + 1.120 x Loge(INR) + 0.643
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Meld Score Predicts 90 Day Mortality
Patient/Graft Survival Among U.S. Liver Transplant Recipients.
69%74%
85% 87%
54%60%
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53 yo male patient with HCV/HIV and alcholic cirrhosis, current MELD score of 20.
BMI is 39.5
History of renal cancer s/p resection 3 yrs (3 cm)
Portal vein thrombosis on ultrasound
Last alcohol use 5 months back (heavy use)
Question
Which is the factor will limit his transplant listing?
1. Obesity, BMI 39.5.
2. HIV.
3. Hx of renal cell cancer.
4. PVT.
5. Alcohol use.
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Which is the factor will limit his transplant listing?
1. Obesity, BMI 39.5 (BMI 40-50 need eval)
2. HIV (HIV/HCV high risk)
3. Cancer (need to see 5 yr survival and recurrence)
4. PVT (Not a contra-indication)
5. Alcohol use (6 months sober)
Key Points Avoid narcotics, sedatives and NSAID’s
Tylenol is safe (max dose 2 grams per day)
Avoid IV fluids (NS). If needed use IV albumin
Low threshold of starting antibiotics
Any change in clinical status need infectious work up and paracentesis
Please monitor stool output on lactulose
Early referral to transplant center
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THANK YOU
“Is life worth living? It all depends on the liver.”William James, American philosopher (1842)
Acute Liver Failure
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Case Presentation
18-year-old woman
Binge-drinking on New Year Eve 1/1: Tired, “hungover”
1/2: Nausea, vomiting, abd pain, moody, sleepy
1/3: Confused, disoriented, agitated, calling people by wrong names, talking to objects
Past History
PMH: asthma, binge drinking
Meds: beclamethasone, albuterol, ranitidine, minocycline
SH: Lives with parents
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Initial Labs
130
4.5 20 1.18103
15.437.7
362
10,299 10,6513.7
199
7.42/35/52
Lactate 5.8NH3 150
INR 7.2
APAP 30
Coagulopathy
INR > 1.5
Encephalopathy
No pre-existing liver disease
Duration < 26 weeks
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Acute Liver Failure
Hep B
Autoimmune HELLP
HSV Wilson Disease
DILI
Acetaminophen
Hep A
CoagulopathyComa
InfectionRenal failureBleeding
CAUSE
EFFECT
Indeterminate
Budd-Chiari
Shock
Etiology of Acute Liver Failure Adult Registry (n = 2,224)
ALF Study Group, Jan 201546%
11%12%
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Acetaminophen cases as % of all ALF per year
Prognosis in ALF: Etiology is a Main
Determinant
Good prognosis:
APAP 66%
Ischemia66%
Pregnancy 55%
Hepatitis A 56%
Transplant free survival rates differ greatly
(Age is NOT an important determinant)*
*Schiødt FV, et al., Liver Transplant 2009
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Prognosis in ALF: Etiology is a Main Determinant
Good prognosis:
APAP 66%
Ischemia 66%
Pregnancy 55%
Hepatitis A 56%
Transplant free survival rates differ greatly
Bad prognosis:
Drugs 27%
Indeterminate 25%
Autoimmune 26%
Hepatitis B 26%
Wilson Disease 0%
(Age is NOT an important determinant)*
*Schiødt FV, et al., Liver Transplant 2009
Specific Therapies
1. Acetaminophen2. Autoimmune3. HBV4. HSV5. Amanita6. Pregnancy
A. NAC/ CharcoalB. CorticosteroidsC.Entecavir/tenofovirD.AcyclovirE. Silibinin/PenicillinF. Delivery
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Initial Management
Must have high index of suspicion at time of admission
Condition progresses rapidly
Changes in consciousness occur hour-by-hour
Admission or early transfer to ICU warranted
Principles of care
Intensive care management of severe, rapidly progressive multi-organ system failure
Only effective treatment: emergent liver transplantRapid psycho-social evaluation critical
Order sets and daily checklists can be used
No substitute for experience
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Treatment for APAP OverdoseN-acetylcysteine (NAC) is an effective
antidote!
IV NAC will totally prevent toxicity if given < 12 hrs
Uncertain benefit after 30 hours
Supportive care in ICU: may develop fatal
complications: brain edema.
Initial evaluation: is it ALF? If so, is he/she a LT
candidate? If so, consider early transfer to OSU.
Acute Liver Failure: An Orphan Disease
Still very rare but interesting!
Requires specialty care
Outcomes improved in recent era
Transplantation still the centerpiece of care
Treatment trials underway; use NAC for all (?)
Recognize the hallmarks of ALF: coma/high INR
Refer early
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≥6 mmHgSinusoidal PHT
Portal Hypertension: HVPG measurement
≥ 12 mmHgVarices & Ascites
Reduction of HVPG to <12 or at least by 20% reduces the risk of rebleeding from 46-65% to 0-13%
Variceal Hemorrhage SuspectedVariceal Hemorrhage Suspected
Initial ManagementInitial Management
NO
Rescue TIPS/Shunt surgeryRescue TIPS/Shunt surgery
Balloon TamponadeBalloon Tamponade
YES
Early rebleeding?Early rebleeding?
Acute Hemorrhage Controlled?Acute Hemorrhage Controlled?
YES
2nd Endoscopy2nd Endoscopy
Further bleeding
NO
Prophylaxis against recurrent hemorrhagProphylaxis against recurrent hemorrhag
Management of Acute Variceal Hemorrhage
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Control of Acute Variceal HemorrhageControl of Acute Variceal Hemorrhage
NO
Surveillance Endoscopyand/or
Life-long Pharmacotherapy
Surveillance Endoscopyand/or
Life-long Pharmacotherapy
Prophylactic Pharmacotherapyand/or
Endoscopic Variceal Band Ligation
Prophylactic Pharmacotherapyand/or
Endoscopic Variceal Band Ligation
Recurrent HemorrhageRecurrent HemorrhageYES
NO YES
Initiate combination RxInitiate combination Rx TIPS/Shunt SurgeryTIPS/Shunt Surgery
Further bleeding
Is patient on EVL + Pharmacotherapy?Is patient on EVL + Pharmacotherapy?
Prophylaxis of Recurrent Variceal Hemorrhage
Infections:Hospitalized Cirrhotic patients
Distribution of 1st Infection’s % of first & second infection(body sites)
CA: community acquiredHCA: hospital acquiredNoso: nosocomial
Bajaj J et al. Hepatology 2012
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Secondary Prevention Variceal Bleeding
The combination of endoscopic therapy with medical therapy is the initial approach to prevent variceal re-bleeding.
Curr Treat Options Gastroenterol. 2002;5(6):471
Liberal vs Restrictive Transfusion Strategy
Villanueva et al, NEJM 2013
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Medical therapyAcute resuscitationIV Vasoactive drugs Antibiotic prophylaxis
Endoscopic therapyBandingInjection therapy
TIPSCovered stent
Garcia-Tsao G. NEJM 2010; 362: 823-832
Therapy for Variceal Bleeding
Epidemiology
Most common complication of cirrhosis
Within 10 years of diagnosis of compensated cirrhosis, 50% of patient with develop ascites
Development of ascites = 50% two year mortality
Diuretic refractory ascites = 50% one year mortality
Development of SBP = 30% one year mortality
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Pharmacologic therapy
Octreotide is superior and safer compared to vasopressin
Octreotide infusion for 5 days prevent early re-bleeding
Endoscopic Variceal Band Ligation
Bleeding controlled in 90%
Rebleeding rate 30%
Compared with sclerotherapy: Less rebleeding
Lower mortality
Fewer complications
Fewer treatment sessions
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TIPS in the Treatment of Variceal Hemorrhage
Recurrent variceal hemorrhage (at second rebleed for esophageal varices, at first rebleed for gastric varices)
Rebleed on combination endoscopic plus pharmacologic therapy (10-20%)
In patients with Child A/B cirrhosis, the distal spleno-renal shunt is as effective as TIPS (dependent on local expertise)
Treatment: Diuretics
Monotherapy spironolactone more successful than use of furosemide alone Loop diuretics depend on secretion into the tubule
for action. Secretion is impaired in cirrhosis Monotherapy spironolactone can cause
hyperkalemia
Optimal regimen: spironolactone 100 mg/d and furosemide 40 mg/d single daily dose Increases should be made every 3-5 days as
needed, maintaining ratio Ratio may need to be < 100/40 in patients with
parenchymal renal disease
Maximum doses: 400 mg/d spironolactone, 160 mg/d furosemide
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Natural History of Hepatorenal Syndrome (HRS)
Arroyo et al., Gastroenterology 2002; 122:1658
5
3
1
0
Months
Creatinine(mg/dL)
6
0 - 4 0 1 3
4
2
- 6 - 2 2Weeks
Type 2 HRS Type 1 HRSSBP
CefotaximeCefotaximeTherapeutic paracentesesTherapeutic paracenteses
Ascites and Hyponatremia are Always Present in HRS
Besides renal failure, patients with HRS have sodium and water retention
Ascites is universal in patients with HRS. If ascites is absent, renal failure is more likely due to other causes
Hyponatremia is almost universal in HRS. If serum sodium is normal, diagnosis of HRS is unlikely
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Overt Hepatic Encephalopathy
Associated with a poor prognosis
Retrospective review of 111 cirrhotic patients for 12±17 months following first episode of acute OHE:
82 (74%) died during follow-up period
Survival probability
42% at 1 year
23% at 3 years
Bustamante J et al. J Hepatol. 1999;30(5):890-895.
The Acute Episode of HE
Supportive care, airway protection
Head imaging
Precipitating causes
Dehydration - lactulose overtreatment?
Missed medication dose(s)
Infection (SBP, UTI)
Specific medical therapy
Transplant candidacy
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RFHE3001 Trial: Rifaximin for Maintaining Remission in Hepatic Encephalopathy
Multicenter, randomized, double-blind, placebo-
controlled, phase III trial of efficacy and safety of
rifaximin 550 mg BID for 6 months in maintenance of
remission in patients with recurrent, overt HE
Cirrhosis and /or portal hypertension
Two or more episodes of HE (Conn score ≥2) within
6 months of screening
Conn score 0 or 1 at screening
NM Bass, KD Mullen, S Sigal, A Sanyal, F Poordad, K Merchant, S Huang, A Shaw, E Bortey, WP Forbes Presented at: 44th Annual Meeting of the European Association for the Study of the Liver; April 25, 2009; Copenhagen, Denmark.
Sepsis MortalityCirrhosis v/s Non cirrhosis
0
10
20
30
40
50
60
70
80
90
Cirrhosis Non cirrhosis
30 day mortality
%
Mortality in Sepsis
60-80%
50%
Fernandez et al. Hepatology 2006; Plessier et al. Liver Int 2003
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Predictors of hemorrhage: Variceal size Red signs Child B/C
NIEC. N Engl J Med 1988; 319:983
Variceal hemorrhage Varix with red signs
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Liver insufficiency
Varicealhemorrhage
Complications of Cirrhosis Result from Portal Hypertension or Liver Insufficiency
Cirrhosis Ascites
Encephalopathy
Jaundice
Portal hypertension
Spontaneous bacterial peritonitis
Hepatorenalsyndrome
HE Clinical Diagnosis
Knowledge of existing liver disease/portosystemicshunting
Precipitating factors
Altered mental state, hypertonicity, asterixis, fetor hepaticus
Reversibility with treatment
Testing to exclude other causes of altered mental state (brain imaging, EEG, lumbar puncture)
No consensus on diagnostic criteria
Mullen et al. Semin Liver Dis. 2007
Blei et al. Am J Gastroenterol. 2001
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Number Needed to Treat
1 of 4 cases of breakthrough HE can be avoided with 6 months of rifaximin (NNT=4)
1 of 9 cases of hospitalization-related HE can be avoided with 6 months of rifaximin (NNT=9)
Bass et al. N Engl J Med. 2010;362:1071-1081.
Routine prophylactic use offresh frozen plasma or platelets before
paracentesis?
In a study of 1100 large volume paracenteses there were no hemorrhagic complications despite a) no prophylactic transfusions, b) platelet counts as low as 19,000 cells/mm3 (19 x 106 /L)(54% <50,000) and c) international normalized ratios for prothrombin time as high as 8.7 (75% >1.5 and 26.5% >2.0)
Grabau CM et al. Hepatology 2004
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One controlled trial randomized patients with SBP to receive cefotaxime alone versus cefotaxime plus 1.5 g albumin per kg body weight within 6 hours of enrollment and 1.0 g/kg on day 3. A decrease in mortality from 29% to 10% was reported
A more recent study has shown that albumin should be given when the serum creatinine is >1 mg/dL, blood urea nitrogen >30 mg/dL, or total bilirubin >4 mg/dL but is not necessary in patients who do not meet these criteria.
MELD
0%
20%
40%
60%
80%
100%
0 5 10 15 20 25 30 35 40
90-d
ay S
urv
ival
MELD
90%
7%
e
INRBilirubinCreatinine
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147
Bacterial Infections in Hospitalized Cirrhotic Patients
0
10
20
30
40
50
60
1980’s Non-cirrhotics
Deschenes(1999)n=140
%
Fernandez(2002)
n=1,567
32%34%
20%
6%
~46%
41%
Dupeyron(2001)n=589
Borzio(2001)n=405
Cirrhosis: ICU admissions
ICU admissions related to cirrhosis in the US is about 26,000 per year with an estimated cost of $3 billion
Olson JC, Kamath PS. Curr Opin Crit Care 2011
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Non-Pharmacologic Treatment of Acute Variceal Hemorrhage
Endoscopic Band Ligation
Transjugular Intrahepatic Portal-systemic Shunting (TIPS)
Mostly Historical Interest Embolization of varices
Injection Sclerotherapy
Questions
What is the risk of variceal bleed in cirrhosis?
What is your goal Hgb/HCT?
Use of IV octreotide? Other medications?
Use of IV antibiotics?
Control of bleeding? Banding vs. medications?
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Acute Variceal Hemorrhage
Labs
130
4.5 20 1.18103
102 1204.5
199
INR 1.6 1219
62
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Treatment: Serial LVP
If patient compliant with diet, should need no more than 8.4 L every two weeks
LVP does result in protein and complement depletion, may indirectly predispose to asciticfluid infection
Every tap should be tested for cell count and differential Prevalence of occult infection low
Evans et al, Hepatology 2003: 3.5%
Lactulose Therapy in HE
Standard of care
Poorly tolerated
Unpalatable
Flatulence and abdominal pain
Diarrhea
Nausea/ Ileus in large doses
Hypernatremia
Gerber T, Schomerus H. Drugs. 2000;60:1353-1370; Mullen KD, Dasarathy S. In: Schiff ER, et al, eds. Schiff’s Disease of the Liver, ed 8. Philadelphia, PA: Lippincott-Raven; 1999, pp 545-581; Williams R, et al. Eur J Gastroenterol Hepatol. 2000;12:203-208.
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140 consecutive cirrhotic patients recovering from a bout of HE
Randomized to lactulose (30-60 ml/day) or placebo (non-blinded)
Primary endpoint = an episode of overt HE
Follow-up 1-20 months (median = 14 mo.)
Lactulose resulted in a 58% reduction in the incidence ofovert HE (p=0.001)
Gastroenterology. 2009;137:885-891
Prevention of Overt Episodic HE: Is Drug Therapy Effective?
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52 year-old man with cirrhosis due to HCV, listed for LT. Complications include ascites and encephalopathy
Labs at time of listing: MELD 17
Which of the following changes in lab parameters will increase his MELD score the most?
INR Bilirubin Creatinine
Baseline 1.5 3.0 1.2
Change in Labs 3 months later
#1 3.0 3.0 1.2
#2 1.5 6.0 1.2
#3 1.5 3.0 2.4
MELD17
251924
Question
Ascites
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Pathophysiology of HRS
Portal hypertension
Splanchnic vasodilation
Low effective arterial blood
volume
BP, no ascites, no edema
Disease progression
Refractory ascites, anasarca, severe
BP
Decompensated Cirrhosis
Renal Failure (HRS)
Renal Failure (HRS)
Compensated Cirrhosis
Adapted from Gines, NEJM 2009.
SBP: Emergence of enterococci
170 episodes of culture positive ascites
Gram +ve infections in 50% cases
Enterococcus spp: 28% cases
Poor survival in enterococcus group
Reuken PA et al. Aliment Pharmacol Ther 2012