Transcript Somatostatin, octreotide and gabexate mesilate in the therapy of

EBM in GI Emergency
Hsiu-Po Wang
Department of Emergency Medicine
National Taiwan University Hospital
EBM in GI emergency
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Non-variceal UGI bleeding
Variceal UGI bleeding
Stress ulcer
Acute pancreatitis
Fulminant hepatic failure/ Hepatic coma
Consensus Recommendations
for
Nonvariceal Upper Gastroinestinal Bleeding
Ann Intern Med. 2003;139:843-857
Categorizaion of Evidence
Quality
of Evidence
Description
I
Evidence obtained from at least 1 properly randomized, control
led trial
II-1
Evidence obtained from well-designed controlled trials without
randomization
II-2
Evidence obtained from well-designed cohort or case-control s
tudies, preferably from more than 1 center or research group
II-3
Evidence obtained from comparisons between times or places
with or without intervention, or dramatic results in uncontrolled
experiments
III
Opinions of respected authorties, based on clinical experience,
descriptive studies, or reports of expert committees
Recommendation
• Immediate evaluation and appropriate resuscitation are cri
tical to proper management
– Evidence: III
Opinions of respected authorties, based on clinical experience, d
escriptive studies, or reports of expert committees
Recommendation - NG tube
• In selected patients, the placement of a NG tube
can be considered because the findings may have
prognostic value.
– Evidence: II-3
Evidence obtained from comparisons between times or places
with or without intervention, or dramatic results in uncontrolled
experiments
Recommendation - NG tube
• The detection of red blood with in-and-out NG:
poor outcome and need for emergency endoscopy
• RUGBE: the presence of bright blood in the aspirate
was an independent predictor of rebleeding
• OG or NG lavage may be helpful to clear the blood
before endoscopy
Recommendation - Clinical stratification
• Clinical stratification of patient into low- and high-risk
categories is important for proper management.
– Evidence: II-2
Evidence obtained from well-designed cohort or case-control studi
es, preferably from more than 1 center or research
group
Recommendation - Clinical stratification
• Rebleeding: > 65 years old, shock, poor overall health status,
comorbid illnesses, low initial hb level, melena, transfusion
requirement. fresh red blood on rectal examination/emesis/NG as
pirate
• Death: > 60 years old, shock, poor overall health status, comorbid
illnesses, low initial Hb level, melena, transfusion requirement.
fresh red blood on rectal examination/emesis/NG aspirate, inset of
bleeding while hospitalized for another reason, sepsis,
↑ BUN/Cre/GOT
• Specialty of attending physician influence the outcome
Recommendation
- Early stratification based on
clinical and endoscopic criteria
• Early stratification of patient into low- and high-risk
categories for rebleeding or mortality, based on clinical
and endoscopic criteria, is important for proper manage
ment.
– Evidence: I
Evidence obtained from at least 1 properly randomized,
controlled trial
Recommendation
- Early stratification based on
clinical and endoscopic criteria
• Laine et al:
clean ulcer base 5%, flat spot 10%, adherent clot 22%,
nonbleeding visible vessel 43%, active bleeding 55%
• Rockall risk score:
age, shock, comorbidity, diagnosis,
endoscopic stigmata of recent bleeding
Recommendation - disposition
• Early endoscopy with risk classification by clinical and
endoscopic criteria allows for safe and prompt discharge
of patients classified as low risk
– Evidence: I
• Improves patient outcomes for patients classified as high
risk
– Evidence: II
• And reduces resource utilization for patients classified as
either low or high risk
– Evidence: I
Recommendation – early endoscopy ?
• Observation study: low-risk patients have no major complication
in those triaged to outpatient care with early endoscopy
• Retrospective cohort trial: hospital stay and need for surgery
with early endoscopy in unselected patients↓
• Randomized, controlled trial: early endoscopy and endoscopic
therapy ↓transfusion, hospital stay in patient with bloody NG
aspirate
• Patient at low risk, high risk, and unselected patients: ↓hosptial s
tay
• Two randomized, controlled trial: Patient at low risk with early
endoscopy 43%~91% ↓ cost
Recommendation
• NIH consensus(1989) and meta-analysis: benefits
of endoscopic therapy mainly examined patients
with high-risk
• Meta-analysis(Bordou et al): endoscopic treatment ↓
rebleeding, surgery, and mortality, compared with drug
or placebo
• Endoscopic therapy for adherent clots ↓ rebleeding
ompared with medical therapy alone
c
Recommendation
- second-look endoscopy
• Routine second-look endoscopy is not recommended
– Evidence: I
– Second-look endoscopy may be of statistical benefit
in select high-risk patients, but data are conflicting
regarding its routine use
– A second endoscopy is ultimately needed in patients
whose initial endoscopic examination is incomplete
Recommendation - rebleeding
• In cases of rebleeding, a second attempt at endoscopic
therapy is generally recommended
– Evidence: I
– Randomized comparison: immediate endoscopic
retreatment in patients with rebleeding after endoscopic
hemostasis ↓need for surgery without increasing the
risk for death and was associated with fewer
complications
Recommendation
- Surgical consultation
• Surgical consultation should be sought for patients who
have failed endoscopic therapy
– Evidence: II-2
Evidence obtained from well-designed cohort or case-control
studies, preferably from more than 1 center or research group
– RUGBE: 14.1% rebleeding, 6.5% required surgery
– Lau et al: 27% of high-risk patient with rebleeding
after endoscopic treatment required salvage surgery
Recommendation
- H2-receptor antagonists
• H2-receptor antagonists are not recommended in the
management of patients with acute UGI bleeding
– Evidence: I
Evidence obtained from at least 1 properly randomized,
controlled trial
Recommendation
- H2-receptor antagonists
• H2-receptor antagonists are not recommended in the
management of patients with acute UGI bleeding
– Meta-analyses(Bardou et al):
no significant improvement in outcomes compared with
other pharmacotherpy or endoscopic therapy
– PPI is more effective than H2-receptor antagonists and
in preventing persistent or recurrent bleeding and
surgery ( in selective patients )
Recommendation
- non-variceal UGI bleeding
• Somatostatin and octreotide are not recommended in
the routine management of patients with acute
non-varoceal UGI bleeding
– Evidence: I
– Meta-analyses: neither somatostatin nor octreotide
improved outcomes compared with other endoscopic
therapy or pharmacotherapy.
Recommendation - PPI
• An iv bolus followed by continuous-infusion PPI is effective
in decreasing rebleeding in patients who have undergone
successful endoscopic therapy.
– Evidence: I
– Randomized trials: high dose bolus and continuous-infusion
PPI have shown ↓rebleeding, ↓need for surgery compared
with H2 blocker or placebo
– Meta-analyses: high dose PPI after successful endoscopic
therapy ↓rebleeding
– RUGBE: PPI ↓rebleeding, mortality in high-risk patient,
trend toward ↓rebleeding in patient with low-risk.
Recommendation - PPI
• In patient awaiting endoscopy, empirical therapy with a
high-dose PPI should be considered.
– Evidence III
Opinions of respected authorties, based on clinical experience,
descriptive studies, or reports of expert committees
– Oral Losec reduce rebleeding with or without decreased
rates of surgery
– RUGBE: some efficacy in patients with both low- and
high-risk endoscopic lesions
Recommendation - feeding
• Patients considered at low risk for rebleeding after
endoscopy can be fed within 24hours
– Evidence: I
– Randomized trial has shown that the time of rebleeding
does not influence the hospital course of patients at low
risk
– Patient with major hemorrhage and endoscopic findings of
a Mallory-Weiss tear or an ulcer with a clean base, flat spot,
or clot may be fed and discharged home immediately after
stabilization
At Patient Presentation
• Immediately evaluate and initiate appropriate
resuscitation
• Consider placement of a NG tube in selected patients
because the findings may have prognostic value
• Stratify patients into low- and high-risk categories for
rebleeding and death on the basis of clinical criteria.
Use available prognostic scales to assist in decision
making
At Endoscopy - I
• Stratify patient into low- and high-risk categories for
rebleeding and death on the basis of clinical and endoscopic
criteria. Use available prognostic scales to assist in decision
making.
• Perform early diagnostic endoscopy (<24hrs) with risk
classification by clinical and endoscopic criteria to assist in
– Safe and prompt discharge of patients at low risk
– Improvement of outcomes for patients at high risk
– Reduction of resource utilization for patients at either low
or high risk
At Endoscopy - II
• Endoscopic hemostatic therapy is not indicated for
patients with low-risk stigmata
• Endoscopic hemostatic therapy is indicated for a
patient with a clot in an ulcer bed, including targeted
irrigation in an attempt at dislodgment, with appropri
ate treatment of the underlying lesion
• Endoscopic hemostatic therapy is indicated for
patients with high-risk stigmata.
Follow-up
• Routine second-look endoscopy is not recommended
• A second attempt at endoscopic therpay is generally
recommended in cases of rebleeding
• Seek surgical consultation for patients in whom
endoscopic therapy has failed
• Patients at low risk after endoscopy can be fed within
24 hours
Pharmacotherapy
• H2-receptor antagonists are not recommended for
patients with acute ulcer bleeding
• Somatostatin and octreotide are not routinely
recommended for patients with acute ulcer bleeding
• IV bolus followed by continuous-infusion PPI can
effectively decrease rebleeding in patients who have
had successful endoscopic therapy
• Consider high-dose PPI for patients awaiting
endoscopy
EBM for
treatment of
variceal bleeding
Treatment of bleeding varices
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Conservative treatment
Balloon tamponade
Somatostatin analogues
Terlipressin
Endoscopic ligation
Endoscopic sclerotherapy
Transjugular intrahepatic portosystemic shunt
( TIPS )
Somatostatin analogues for acute
bleeding oesophageal varices
• Treating bleeding oesophageal varices with somatostatin a
nalogues does NOT appear to reduce deaths, but may le
ssen the need for blood transfusions
The Cochrane Database of Systematic Reviews 2005 Issue 1
Terlipressin for acute esophageal
variceal hemorrhage
• 20 RCT included
• A statistically significant reduction in mortality compared
to placebo (relative risk 0.66, 95% confidence interval
0.49 to 0.88)
• Terlipressin vs somatostatin or terlipressin vs endoscopic
Tx  no statistically significant difference
• Terlipressin vs balloon tamponade, terlipressin vs
o
ctreotide, and terlipressin vs vasopressin ( small, low q
uality studies )  no difference in any of the major
o
utcomes
The Cochrane Database of Systematic Reviews 2005 Issue 1 (meta-analysis)
Terlipressin for acute esophageal
variceal hemorrhage - Summary
• Terlipressin appears to be as safe as other treatments
• Terlipressin may reduce the mortality from variceal
leeding as compared to placebo
b
• No sufficient data to decide whether terlipressin was
better or worse than other available treatments such as
other drugs (somatostatin, octreotide) or endoscopic Tx
The Cochrane Database of Systematic Reviews 2005 Issue 1 (meta-analysis)
Endoscopic ligation vs pharmatherapy
for acute bleeding oesophageal varices
• Ligation is the most effective treatment option.
• No significant difference was found between the
fficacy of sclerotherapy and treatment with
tostatin or octreotide
e
soma
Endoscopy 2001;33(9): 737-46 (meta-analysis)
Sclerotherapy vs medical interventions for
bleeding oesophageal varices
in cirrhotic patients
• No convincing evidence to support the use of
emergency sclerotherapy for variceal bleeding
in cirrhosis as the first, single treatment when
compared with vasoactive drugs.
The Cochrane Database of Systematic Reviews 2005 Issue 1
TIPS compared with endoscopic treatment
for prevention of variceal rebleeding
• Variceal rebleeding more frequent with ET (46.6%) than w
ith TIPS (18.9%)
• Post-treatment encephalopathy occurred significantly less
often after ET (19%) than after TIPS (34%)
• TIPS compared with ET reduces the rebleeding rate, but
does not improve survival, and increases the incidence of
encephalopathy in a period of 1 to 2.5 years
Hepatology 1999;30(3):612-622 (meta-analysis )
Summary of Tx of bleeding varices
• Treatment modalities are better than placebo
• Endoscopic ligation may be the best option of treatment
• Endoscopic sclerotherapy is not better than medications
• Medications such as somatostatin, octreotide, terlipressin
are safe in treatment of bleeding varices
• No difference between somatostatin, octreotide, and
terlipressin
• TIPS ( compare with endoscopic Tx ) reduces rebleeding
rate, but increases in the incidence of encephalopathy
EBM in GI emergency
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Non-variceal UGI bleeding
Variceal UGI bleeding
Stress ulcer
Acute pancreatitis
Fulminant hepatic failure/ Hepatic coma
Opinions about stress ulcers
• Stress ulcer bleeding is uncommon
• Can occur in spite of prophylactic treatment
• Should be considered as markers of prolonged sur
vival in critically ill patients, rather than untreatable
complications
Studies of stress ulcers
• More than 100 studies of the frequency, risk
factors, and prophylaxis.
• These subjects continue to generate controversy.
• Why? Study methods, bleeding definition,
patient population & number, and so on.
• Cushing’s ulcer
# associated with CNS injury
# single deep lesion in the duodenum or stomach
• Curling’s ulcer
# associated with thermal injury
# may appear in the esophagus, stomach, small
bowel & colon
Frequency of stress ulcer bleeding
• Varies ( decrease recent years )
• Adult
Before 1978, 5.3% - 33%
1978-1984
1.6% - 39%
1984-1994
0.1% - 39% ( average 6% )
• Pediatric population
Clinical important bleeding: 20% in control group
5.7% in treated group
Recommendation#1 (Adult )
Prophylaxis for general ICU patients
Coagulopathy
platelet < 50000 mm3
PT > 2X control
 Mechanical ventilation
> 48 hours
 History of GI ulcer or bleeding
with one year
At least 2 following risk factor:
Sepsis
ICU stay > 1 week
Occult bleeding > 6 D
High-dose corticsteriod
>250mg/D
ASHP Therapeutic Guidelines
Recommendation#1 (Pediatrics)
Prophylaxis for general ICU patients
• No definite conclusion :
prophylaxis provides protection
• Risk factors:
respiratory failrue
coagulopathy
Shock
Surgery> 3 hr
Trauma
Pediatric Risk of Mortality score
> or /& = 10
ASHP Therapeutic Guidelines
Recommendation#2 (Adult)
Prophylaxis for special populations
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Glasgow Coma Score < or/&= 10
Thermal injury > 35% of BSA
Partial hepatectomy
Multiple trauma:
Injury Severity Score > or/&=16
• Transplatation patients perioperatively
• Hepatic failure
• Spinal cord injury
ASHP Therapeutic Guidelines
Recommendation#2 (Pediatrics)
Prophylaxis for special populations
• Thermal injury ( what BSA ?)
• For other pediatric surgery or trauma,
insufficient evidence to recommend prophylaxis.
ASHP Therapeutic Guidelines
Recommendation#3 (Adult)
Medications for prophylaxis
• Conflicting results of meta-analyses & recent RCT
• Choice among antacid, H2-antagonists, sucralfate:
made on an institution-specific basis
• Insufficient data on misoprostal or PPI
ASHP Therapeutic Guidelines
Prophylactic agents for stress ulcer
• Inhibition of gastric acid secretion
H2 antagonist, PPI, prostaglandin analogue(?)
• Neutralization of gastric acid
anatacid
• Protective mechanism
sucralfate, misoprostol
• HSP70 inducer (GGA), free-radical scavenger(?)
Prophylaxis for overt bleeding (I)
Mx 1
Mx 2
Result
H2-receptor
antagonists
VS placebo or
no therapy
significantly
reduced
OR 0.58 (95%
CI: 0.42, 0.79)
H2-receptor
antagonists
VS antacid
significantly
reduced
OR 0.44 (95%
CI: 0.37, 0.84)
Sucralfate
VS no prophylaxis decreased
OR 0.58 (95%
CI: 0.34, 0.99)
Antacids
VS placebo or
no therapy
Not statistically
significant
A trend favour
of antacids
Database of Abstracts of Reviews of Effects 2005 Issue 1
JAMA 1996;275(4):308-314 Sixty-three RCTs
Prophylaxis for overt bleeding (II)
Mx 1
Mx 2
Result
Sucralfate
VS antacids
No differential effectiveness
Sucralfate
VS H2-receptor
antagonists
No differential effectiveness
Database of Abstracts of Reviews of Effects 2005 Issue 1
JAMA 1996;275(4):308-314 Sixty-three RCTs
Prophylaxis for clinically-important bleeding
Mx 1
Mx 2
Result
H2-receptor
antagonists
VS placebo or
no therapy
significantly
reduced
OR 0.44 (95%
CI: 0.22, 0.88)
H2-receptor
antagonists
VS antacid
No statistically-significant
although a trend in favour of H2receptor antagonists
Database of Abstracts of Reviews of Effects 2005 Issue 1
JAMA 1996;275(4):308-314 Sixty-three RCTs
Meta-analyses for Risk of Pneumonia with Medications of SUP
Tryba M J Clin Gastroenterol
1991;13(suppl 1):S44-55
Tryba M Crit Care Med
1991;19:942-9
Cook DJ Chest 1991;100:7-13
Cook DJ Infect Control Hosp
Epidemiol 1994;15:437-42
Cook DJ JAMA
1996;275:308-14
sucralfate
vs H2-antagonist
or antacid
sucralfate
vs H2-antagonist
& antacid
sucralfate
vs H2-antagonist
or antacid
sucralfate
vs H2-antagonist
or antacid
sucralfate
vs control
antacid
H2-antagonist
lower rate
with
sucralfate
lower rate
with
sucralfate
not favored
sucralfate
lower rate
with
sucralfate
not favored
sucralfate
Incidence of pneumonia
- Prophylaxis for stress ulcer
Mx 1
Mx 2
Result
Sucralfate
VS H2-receptor
antagonists
a trend toward a lower incidence
of pneumonia
Sucralfate
VS antacid
a trend toward a lower incidence
of pneumonia
H2-receptor
antagonists
VS no prophylaxis increased incidence of pneumonia
not statistically significant
Database of Abstracts of Reviews of Effects 2005 Issue 1
JAMA 1996;275(4):308-314 Sixty-three RCTs
Mortality
- Prophylaxis for stress ulcer
Mx 1
Mx 2
Result
Sucralfate
VS H2-receptor
antagonists
a trend in favour of sucralfate
Sucralfate
VS antacid
statistically-significant reduction in
mortality , OR 0.73 (95% CI: 0.54,
0.97)
Database of Abstracts of Reviews of Effects 2005 Issue 1
JAMA 1996;275(4):308-314 Sixty-three RCTs
Recommendation#3
(Pediatrics & special group)
Medications for prophylaxis
• Lack of comparative trials of prophylactic agents
• The choice of agents should be made on an instit
ution-specific basis: administration, adverse effec
ts & total cost
ASHP Therapeutic Guidelines
Recommendation#4 (Adult & Pediatrics)
Adverse-effects of prophylaxis
• History of serious reactions to prophylactic agents
• Sucralfate & antacid: avoid in neonates
bezoar formation, accumulation of Al & Mg
• Al-contained agents avoided in children with renal
impairment
• Acid-suppression agent associated with high rate of
pneumonia than suvralfate (?)
• Adverse effect - part of economic analysis
ASHP Therapeutic Guidelines
Recommendation#5 (Adult & Pediatrics)
Prevention of rebleeding
• Lack of available trials prohibits definite
recommendations for preventing recurrent bleeding
• Consideration could be given to increase dosage,
add other medication or switch to a different agent
ASHP Therapeutic Guidelines
Recommendation#6 (Adult & Pediatrics)
When to discontinue prophylaxis
• Prophylaxis can be stopped once risk factors have
resolved
extubation or discharge from ICU
ASHP Therapeutic Guidelines
Enteral feeding & TPN- risk factor ?
• Previous studies have different results
due to differences in location of enteral feeding tubes
• Enteral feeding: augment mucosa defense & neutralize
gastric acid
Crit Care Med 1983;11:13-6
• Not related to the use of TPN
Armstrong TA, et al. Am J Health-Syst Pharm 1999;56:347-79
Ben-Menachem T, et al. Ann Intern Med 1994;121:568-75
EBM in GI emergency
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Non-variceal UGI bleeding
Variceal UGI bleeding
Stress ulcer
Acute pancreatitis
Fulminant hepatic failure/ Hepatic coma
EBM in acute pancreatitis
• Pharmacotherapy in acute pancreatitis
• Anti-acid treatment for acute pancreatitis
• Antibiotics prophylaxis for acute pancreatitis
• Early ERCP + EST for acute biliary
pancreatitis
• Early feeding for acute pancreatitis
Two mortality peaks of severe acute pancreatitis
Mortality
infection
MOF
1st – 2nd week
3rd – 4rd week
Question :
Does the patient
with acute necrotizing pancreatitis
benefit from
using specific drugs ?
Specific pharmacologic therapy
of Acute Pancreatitis
• Antiproteolytic agent
Aprotinin
FFP
Gabexate mesilate
• Anti-inflammatory agent
Lexipafant
• Inhibitor of exocrine
secretion
Glucagon
Cacitonin
Atropine
Somatostatin
Octreotide
RCTs of Antiproteolytic and Anti-inflammatory Agents in Acute Pancreatitis
Trial
Agent
Effect
Trapnell et al., 1974
Aprotinin
Morbidity↓, mortality↓
MRC, 1977
Aprotinin
No effect
Imrie et al., 1978
Aprotinin
No effect
Leese et al., 1991
Fresh frozen plasma
No effect
Valderrama et al., 1992
Gabexate mesilate
No effect
Buchler et al., 1993
Gabexate mesilate
No effect
McKay et al., 1997
Lexipafant
Organ failure score↓
Lexipafant
No effect
Johnson CD et al., 2001
( Gut 48:62-9 )
RCTs of Modifiers and Inhibitors of Secretion in Acute Pancreatitis
Trial
Agnet
Effect
Olazabal and Fuller, 1978
Glucagon
No benefit
Debas et al., 1980
Glucagon
No benefit
Kronborg et al., 1980
Glucagon
No benefit
Goebell et al., 1979
Calcitonin
No benefit
Cameron et al., 1979
Atropine
No benefit
RCTs with Somatostatin and Octreotide (with more than 20 recruited patients)
Trial
Drug
Complication (%)
Mortality (%)
Choi et al., 1989
Som/C
2.9
5.6
Gjorup et al., 1992
Som/C
42
3
30
3
Mitrovic et al., 1993
Som/C
33 (<0.05)
20
58
40
Luengo et al., 1994
Som/C
2
2
O’Hair et al., 1993
Oct/C
3
1
10
0
Italian Study Group, 1994
Oct/C
6 (=0.05)
2
16
5
Paran et al., 1995
Oct/C
26 (=0.04)
11
74
37
McKay et al., 1997
Oct/C
55
18
37
20
Uhl et al., 1999
Oct 300ug/d
76
15
Oct 600ug/d
72
12
C
71
16
Somatostatin, octreotide and gabexate mesilate
in the therapy of acute pancreatitis ?
No agent was proven to be of value in the treatment of mild
acute pancreatitis.
Both SS and OCT
beneficial in improving the overall mortality in severe acute
pancreatitis
no significant effect on complication rate
FOY
no effect on either early or overall mortality
effective in improving the complication rate, and the number
of cases submitted to surgery
Alimentary Pharmacology and Therapeutics 1998;12(3):237-245 ( Meta-analysis)
Somatostatin, octreotide and gabexate mesilate
in the therapy of acute pancreatitis ?
• 14 and 3 negative studies for somatostatin
and octreotide, respectively
• Conclusions should therefore be interpreted
with caution.
Recommendation
• In mild, self-limited, acute pancreatitis,
no specific pharmacologic treatment is
indicated.
• Current evidence dose not support the
use of specific pharmacologic agents
( antiproteases, anti-inflammatory
agents, secretory inhibitiors) in severe
acute pancreatitis
Combining antisecretory agents
with antiproteases would be of
great benefit in patients with severe
acute pancreatitis ?
Conservative Treatment of
Acute Pancreatitis
• Nasogastric suction & nil per os
 prospective in morbidity,
mortality & length of hospital days
# but small number, restricted to alcoholic
pancreatitis randomized studies
# no significant benefit
• H2-receptor antagonists
 RCTs failed to show clinical benefit
Histamine-2 receptor antagonists for
acute pancreatitis ?
• Five placebo-controlled RCTs (285 patients)
• Parenteral cimetidine was evaluated
• No statistically-significant difference in
complication rates between cimetidine and
placebo
• No statistically-significant difference in the mean
duration of pain between cimetidine and placebo
• Rather, the use of cimetidine associated with
higher rates of complications and pain
Eur J Gastroenterol Hepatol 2002;14(6):679-686 (meta-analysis )
Histamine-2 receptor antagonists for
acute pancreatitis ?
• Routine use of cimetidine should be
abandoned until the safety and efficacy of
H2RAs are proven
Eur J Gastroenterol Hepatol 2002;14(6):679-686 (meta-analysis )
Question :
Does the patient
with acute necrotizing pancreatitis
benefit from
the administration of
antibiotic prophylaxis ?
Two mortality peaks of severe acute pancreatitis
Mortality
infection
MOF
1st – 2nd week
3rd – 4rd week
Why antibiotics ?
INFECTION
• Develop in 40 to 70 % of patients during
the course of necrotizing pancreatitis
• One of the principal complications of
acute pancreatitis
• Combination of sepsis or sepsis-related
MOF --- mortality up to 50 %
Prophylactic antibiotic reduces sepsis and
mortality in acute necrotizing pancreatitis ?
• Three RCTs (n=160) were included
• Relative risk reduction (RRR), absolute risk
reduction (ARR) and number-needed-to-treat (NNT)
Pancreas 2001;22(1):28-31 meta-analysis
Prophylactic antibiotic reduces sepsis and
mortality in acute necrotizing pancreatitis ?
• Local pancreatic infection: the RRR was 31% (95%
CI: -14, 60), the ARR was 12% (95% CI: -2.4, 26.4),
and the NNT was 8 (95% CI: number- needed-to-harm
41, NNT 4)
• Sepsis: the RRR was 46% (95% CI: 15, 70), the ARR
was 21.1% (95% CI: 6.5, 35.6), and the NNT was 5
(95% CI: 3, 15)
• Mortality: the RRR was 72% (95% CI: 40, 100), the
ARR was 12.3% (95% CI: 2.7, 22), and the NNT was 8
(95% CI: 5, 37)
Pancreas 2001;22(1):28-31 meta-analysis
Prophylactic antibiotic reduces sepsis and
mortality in acute necrotizing pancreatitis ?
• Severe pancreatitis should be evaluated with a
rapid bolus, contrast-enhanced computed
tomography scan to look for pancreatic necrosis
• Patients with pancreatic necrosis should be
started on prophylactic antibiotics to prevent
infection in ANP
• This should reduce the morbidity
Pancreas 2001;22(1):28-31 meta-analysis
Prophylactic antibiotic reduces sepsis and
mortality in acute necrotizing pancreatitis ?
• Imipenem (500 mg, three times daily)
• Cefuroxime (1.5 g, three times daily)
• Combination of loxacin (200 mg, twice daily)
 metronidazole (500 mg, twice daily)
Pancreas 2001;22(1):28-31 meta-analysis
Prospective RCTs of Prophylactic Antibiotic Treatment in Severe Acute Pancreatitis
NonPancreatic
pancreatic
Infection
Infection
MOF
Mortality
Trial
Drug
(%)
(%)
(%)
(%)
Pederzoli et al., 1993
Imipenem
12*
15*
29
7
Control
30
49
39
12
Sainio et al., 1995
Cefuroxime
Control
30
40
Mean 1.0†
Mean 1.8
Delcenserie et al., 1996
Ceftazidime/
Amikacine/
0†
9
Control
58
25
Ofloxacin/
61
0
3†
23
Metronidazole
Schwarz et al., 1997
Metronidazole
Luiten et al., 1995
Control
53
15
Oral and rectal SDD/
18
22
38†
35
IV cefotaxime
Control
*p < 0.1 †P = 0.03
Prophylactic antibiotic in acute
necrotizing pancreatitis ?
• Conclusions should be treated with some
caution owing to limitations in the search
(Pancreas 2001;22(1):28-31)
• Large multicentre RCT, seems warranted to
confirm the findings of this meta-analysis study
(Pancreas 2001;22(1):28-31)
Prophylactic antibiotics
for severe acute pancreatitis
• Study designs of evaluations included:
prospective randomised and non-randomised
controlled trials (RCTs), retrospective cohort
studies; prospective case series with historical
control; case control; and retrospective review
with historical control. ranged from 1973 to 1997
• To determine the effectiveness of prophylactic
antibiotics in preventing the infectious
complications of acute pancreatitis
Pharmacotherapy 1999;19(5):592-602
Prophylactic antibiotics
for severe acute pancreatitis
• Earliest four studies were published in the 1970s
and none reported any difference in rates of
development of infection between treatment
groups
• Four most recently completed studies (including 3
RCTs and one retrospective review) in the 1990s
all reported a decrease in overall infectious
complications in patients with moderate to severe
disease
Pharmacotherapy 1999;19(5):592-602
Early Studies of Antibiotic
Prophylaxis
• Craig RM et al.,
Ann Intern Med 1975
Howes R et al.,
J Surg Res 1975
Finch WTR et al. Ann Surg 1976
• Result: prophylaxis not beneficial over
placebo
BUT : 1. small sample size
2. with mild disease
3. wrong antibiotics -- ampicillin
Prophylactic antibiotics
for severe acute pancreatitis
• Alone or in combination:
– Amino glycosides
– Ampicillin
– Imipenen
– Cefuroxime
– Ceftazidime, Amikacin, Metronidazole
Pharmacotherapy 1999;19(5):592-602
Prophylactic antibiotics
for severe acute pancreatitis
• Antibiotics should be administered to patients
with severe disease (based on Ranson criteria
and CT findings)
– Ranson score of 3 or more
– two or more acute fluid collections
– necrosis involving one third or more of the
pancreas
Pharmacotherapy 1999;19(5):592-602
Recommendation
• Antibiotic prophylaxis is justified in
patients with pancreatic necrosis
• Antibiotic prophylaxis should be given
early in the disease ( within 96 hours
after onset )
• Duration: at least 14 days,
preferably continued for 3-4 weeks
Recommendation
• Imipenem is the one with the highest
efficacy factors of all available agents
• SDD : Effective in combination with
intravenous antibiotics.
But dosage, choice & duration
unclear
Early ERCP + EST in gallstoneassociated acute pancreatitis ?
Early ERCP + EST is known to
have complications such as
procedure-related pancreatitis
RCTs of early ERCP for acute pancreatitis
Study
Period Case No.
Study design
Study results
•Safe procedure
•Mortality significantly  in
severe AP ( 24% vs. 61% )
UK
1983-7
121
Single center
Hong Kong
198891
195
•Single center
•Significantly  biliary sepsis
•Some with non- •Mortality significantly  in ABP
biliary etiology
( 0%vs. 12% )
Germany
198994
238
•Multicenter
•ABP patients
•Bil. > 5 mg/dl
excluded
•Mortality similar
•Early ERCP group with 
severe complications Early
•ERCP group non-significantly
increased in Mortality
Poland
198495
280
•Single center
•ERCP+EST for
stone impaction
Early ERCP significantly  both
morbidity ( 17% vs. 36% )and
mortality ( 2% vs. 13% )
ERCP in gallstone-associated acute pancreatitis
• Cochrane Library (Issue 4 2003), Medline (1966-2004),
EMBASE (1980-2004) and LILACS. 'Grey literature'
was sought by looking at cited references and hand
searched to identify further relevant trials. Conference
proceedings of United European Gastroenterology
Week (published in Gut) and Digestive Disease Week
(published in Gastroenterology)
• Randomized controlled trials (RCT) of adult patients,
from 15 years old or greater
The Cochrane Database of Systematic Reviews 2005 Issue 1
ERCP in gallstone-associated acbute pancreatitis
• Controlled for confounding due to associated
acute cholangitis
The Cochrane Database of Systematic Reviews 2005 Issue 1
ERCP in gallstone-associated acbute pancreatitis
• Early ERCP +/- ES :
– Non-significant effect on reduction of mortality
in predicted mild (OR = 0.62, 95% CI = 0.27 to
1.41) and severe GAP (OR = 0.62, 95% CI =
0.27 to 1.41)
– Reduction in complications was nonsignificant in predicted mild (OR = 0.89, 95%
CI = 0.53 to 1.49), but significant in severe
GAP (OR = 0.27, 95% CI = 0.14 to 0.53)
The Cochrane Database of Systematic Reviews 2005 Issue 1
ERCP in gallstone-associated acute pancreatitis
• PATIENTS WITH A PREDICTED SEVERE ATTACK OF
GALLSTONE-ASSOCIATED ACUTE PANCREATITIS
NEED EARLY ENDOSCOPIC RETROGRADE
CHOLANGIOPANCREATOGRAPHY
The Cochrane Database of Systematic Reviews 2005 Issue 1
Nutrition problem in acute
pancreatitis
• About 80 % patients with mild course &
return to oral diet in within 7 days
( AJG 1999;86:1385-91 )
• 10-20 % patients with severe course liable
to prolonged gastroduodenal atony
• Initially withdraw from enteral feeding to
avoid meal-stimulated pancreatic
secretion
---- no evidence-based evaluation
Question :
Does nutrition support improve
the outcome?
Should the patient receive enteral
or total parental nutrition ?
Studies of TPN in Acute Pancreatitis
• Most studies were poorly controlled, nonrandomized, & often retrospective.
• Lipid components : safe to use in patients
with acute pancreatitis ( Case series )
• TPN decreases morbidity, mortality in
patients with acute pancreatitis ?
Two prospective, non-randomized studies : yes
Sitzman JV et al.,
Surg Gynecol Obstet 1989
Kalfarentzos FE et al.,
J Am Coll Nutr 1991
RCTs of comparing TPN with no nutrition support
Trial
Result
Commands
Koretz RL et al., 1997
No benefit
mild cases
Gastroenterology; 113:1414-5
Sax HC et al., 1987
Am J Surg 1987;183:117-24
* : longer hospitalization in TPN group
No benefit*
catheterrelated sepsis
Why Enteral Feeding in Acute Pancreatitis?
• Significant morbidity and mortality in acute
pancreatitis related to sepsis --- arising
from bacteria translocation.
• Enteral nutrition may maintain bowel wall
integrity and reduce bacterial translocation
• TPN with NPO increases intestinal mucosal
permeability, bacterial translocation, &
decreases GI Ig. Alverdy JC et al., Surgery 1988
Li J et al., J Trauma 1995
How Is Enteral Nutrition Given ?
• Suggest that nutrition should be delivered
below the ligament of Treitz
Pisters PW et al., Surg Gynecol Obstet 1992
• Enteral access gained by nasojejunal tube,
percutaneous endoscopic gastrostomy/jejunostomy
surgical gastrostomy/jejunostomy
RCTs of TEN vs. TPN
Trials
Result
McClave SA et al., 1997
No difference in pain scores, days to diet
by mouth, nosocomial infection. Mean Ranson
scores, APACHEⅢ, MOF scores decreased in
TEN group (TEN as safe & effective but
less cost 4X)
Kalfarentzos F et al., 1997
Few total complications (p<0.05)
and septic complications (<0.01) in TEN
TEN less cost 3X
Windsor AC et al., 1998
Disease severity scores (CRP, APACHEⅡ)
improved in TEN but CT score : not. SIRS,
sepsis & MOF all improved in TEN.
Recommendation
• Predicted to return to oral diet within l wk
( Ranson score2 or APACHEⅡ9 ),
nutrition support not indicated
• TEN is as safe & effective as TPN, and
less complications & cost
• Suggest gastrojejunal feeding when TEN
Recommendations for the Management of Severe Acute Pancreatitis
Effect
Level of Evidence
Antiproteases
Not beneficial
1B
Anti-inflammatory agent
Not beneficial
1B
Somatostatin/octreotide
Not beneficial
1A
Pharmacologic therapy
Prophylactic antibiotics
Intravenous antibiotics (imipenem) Reduction of complications 1B
SDD/intravenous cefotaxime
Duration 14 to 28 days
Reduction of mortality
1C
2B
Recommendations for the Management of Severe Acute Pancreatitis
Effect
Level of Evidence
EN
Reduction of mortality
2C
TPN
Reduction of mortality
2C
Safety of EN versus TPN
Reduction of complications
1B
Reduction of mortality
2A
Infected pancreatic necrosis
Reduction of mortality
2A
Late versus early intervention
Reduction of mortality
1B
Nutritional support
Nonsurgical treatment (intensive care)
Sterile pancreatic necrosis
Surgical intervention
Question :
Does the patient
benefit from surgical
intervention ?
Timing of surgery ?
Surgical or Non-surgical Intervention
for Acute Pancreatitis
• First quarter of the 20th centry
 surgery  high mortality & morbidity
• Non-surgical approach followed until late
1960s
• A small group of patients with severe form
profit from surgery
( analysis of disease process )
Surgical or Non-surgical ?
• First consideration :
Infected or sterile
• Infected pancreatic necrosis
 accepted indication for operation
• Sterile pancreatic necrosis
 a matter of controversy
Recommendation
- Determination of Pancreatic Necrosis & Infection
• For detection of necrosis
 CT scan indicated within 48 to 96 hours
after onset *****
• FU CT scan repeated weekly only if
clinical status deteriorates or fails to
improve
Recommendation
- Determination of Pancreatic Necrosis & Infection
• For detection of infection
 FNA of pancreatic necrosis indicated when
# deterioration of clinical status: fever
# lab. status : leukocytosis, increase of CRP
• If clinically not improved
 repeat FNA, once per week
Nonsurgical management for
necrotic pancreatitis
• Buchler MW et al., Ann Surg 2000 ( level 2 )
N=86 ( infected necrosis=29, noninfected=57 )
Surgical intervention for infected group
Nonsurgical approach for noninfected group
Result : mortality surgical group 24%
non-surgical group 1.8%(<.01)
Non-surgical management for sterile necrosis
Surgical Intervention for Infected
Pancreatic Necrosis ?
• Infection of pancreatic necrosis
 an absolute indication for operation
 non-surgical mortality may be up to 100%

Bradley ELD et al., World J Surg 1985
Beger HG et al., Gastroenterology 1986
Beger HG at al., Br J Surg 1988
Surgical Intervention for Sterile
Pancreatic Necrosis ?
• Uncontrolled, retrospective studies ( small )
 no benefit for surgery
Bradley ELD et al., World J Surg 1985
Karimgani I et al., Gastroenterology 1992
• “ non-responsiveness to maximal intensive unit
treatment “ - 72 hours -indication for surgery
Gebhardt C et al., Chirurgie 1994
Timing of Surgery - Early or Late ?
• The only RCT
Rau B et al., J Am Coll Surg 1995;181:279-88
N=41 randomly allocated to
# early necrosectomy ( 48-72 hrs after onset )
# late necrosectomy ( at least 12 D after onset )
early termination of the study due to high OR
( 3.4 times ) in early surgery group
Recommendation
• Infected pancreatic necrosis
 indication for surgery
• Sterile pancreatic necrosis
 undergo conservative treatment
 surgery necessary in selected cases
critical illness for more than 4 weeks
• Early surgery ( within 14 days after onset )
is not recommended in sterile necrosis
Timing of Surgery - Early or Late ?
• Early intensive conservative treatment with late
necrosectomy
current rational approach in severe acute
pancreatitis
• Surgical treatment should be postponed as
long as response to conservative treatment
• Only rare proven early infected necrosis or
unusual complicationsurgent early operation
EBM in GI emergency
•
•
•
•
•
Non-variceal UGI bleeding
Variceal UGI bleeding
Stress ulcer
Acute pancreatitis
Fulminant hepatic failure/ Hepatic coma
Fulminant Hepatic Failure
• A syndrome of rapid progressing liver failure encephalopathy within 8 weeks.
( Trey & Davidson 1970 )
• Characterized by encephalopathy, vasoparesis,
coagulopathy,
then cerebral edema, renal failure, infection
• Causes of death: two main groups
# cerebral edema
# sepsis & MOF
Ward Management or
Intensive Care Management ?
• No controlled clinical trials
• BUT considering almost 100%
mortality before modern intensive care
unit available
(Lucke B et al., Am J Pathol 1946;22:867-945)
 better to be cared in ICU
Management of FHF
• Supportive care
- fluid resuscitation & vasopressor
- mechanical ventilation
- sedation & paralysis
- enema, disaccharides, nutrition(BCAA)
- antibiotic prophylaxis
• Management of cerebral edema
• Management of renal failure
Question :
Which fluid regimens
is better for FHF?
Fluid Resuscitation for FHF
• FHF develops marked hemodynamic change
 vasodilatation - relative hypovolemia
• No controlled clinical trials
• Recent reviews : excess mortality associated
with colloid & albumin -- been criticized
Schierhout G et al., Br Med J 1998;316:961-4
CIGAR Br Med J 1998;317:235-40
Vasopressor good for FHF ?
• Dopamine:
In high cardiac output hypotension ( FHF ),
low dose dopamine dose not  renal
perfusion
but divert blood flow from gastric mucosa
• Dobutamine improve splanchnic blood flow
• Epinephrine & norepinephrine improve MAP
in FHF
Question :
Is mechanical ventilation
needed ?
How about sedation &
paralysis ?
Mechanical ventilation
• Not for hypoxemia
• For airway compromise
-- from grade II to III encephalopathy, at risk
for aspiration
• Hyperventilation for cerebral edema
-- not shown any advantage in long-term
control ICP in FHF
( Ede RJ et al., J hepatol 1986;2:43-51)
Sedation & paralysis needed ?
• Patients with FHF - agitation & aggressive
behavior
• No clinical controlled studies
• Deep sedation – unnecessary ( C )
• Complicated with infection & necrotizing
myopathy
-- no indication for routine paralysis
Interventions for paracetamol
(acetaminophen) overdoses
• RCTs on interventions for paracetamol overdose.
• Activated charcoal seems the best choice to
reduce paracetamol absorption.
• N-acetylcysteine should be given to patients
with paracetamol overdose.
• No N-acetylcysteine regime has been shown to
be more effective than any other.
The Cochrane Database of Systematic Reviews 2002, Issue 3. Art. No.: CD003328
Nonabsorbable disaccharides for
hepatic encephalopathy
• Enema
• Oral
Enema - nonabsorbable disaccharides
for hepatic encephalopathy
• Cleaning of colon is rapid and effective
procedure to remove ammoniagenic
substrates
• 2 double-blind RCTs: favorable response ( A )
Gastroenterology 1981;81:101-6
Heaptology 1987;7:639-43
• Interestingly, enema with tap water was
ineffective ( acidification works ?! )
Oral nonabsorbable disaccharides
for hepatic encephalopathy
• Compared with placebo or no intervention,
nonabsorbable disaccharides had no statistically
significant effect on mortality (RR 0.41, 95% CI
0.02 to 8.68, four trials)
• Trials of high methodological quality
 no significant effect of nonabsorbable
disaccharides on the risk of no improvement of
hepatic encephalopathy (RR 0.92, 95% CI 0.42
to 2.04, two trials)
The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044
Oral nonabsorbable disaccharides
for hepatic encephalopathy
• Nonabsorbable disaccharides appeared to be
inferior to antibiotics on reducing the risk of no
improvement of hepatic encephalopathy (RR
1.24, 95% CI 1.02 to 1.50, 10 trials)
The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044
Summary
- Nonabsorbable disaccharides for hepatic encephalopathy
• The efficacy of lactulose or lactose enema is
beyond any doubt
• There is insufficient evidence to confirm or exclude
whether oral nonabsorbable disaccharides have an
effect on patients with hepatic encephalopathy
• The effect was not seen when only trials of high quality
were analysed.
• Antibiotics appeared to be superior to nonabsorbable
disaccharides in improving hepatic encephalopathy
The Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003044
Neomycin for hepatic encephalopathy
• Neomycin as a standard Tx of HE for about 40
years
• So far, no evidence that neomycin is effective
• The only RCT with placebo  negative result
Hepatogastroenterol 1992;29:542-5
• Combination of neomycin with lactulose was not
superior to placebo
Heaptology 1992;15:222-8
Branched-chain amino acids
for hepatic encephalopathy
• Hepatic encephalopathy may be caused by a
decreased plasma ratio of branched-chain
amino acids (BCAA) to aromatic amino acids.
• Treatment with BCAA was proposed with a
beneficial effect on patients with hepatic
encephalopathy
The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939
Branched-chain amino acids
for hepatic encephalopathy
• 7 randomised trials (556 patients) assessing BCAA
versus carbohydrates, neomycin / lactulose, or
isonitrogenous control
• Compared to the control regimens, BCAA significantly
increased the number of patients improving from
hepatic encephalopathy
• No evidence of an effect of BCAA on survival (RR 1.06,
95% CI 0.98 to 1.14, eight trials) or adverse events
(RR 0.97, 95% CI 0.41 to 2.31, three trials)
The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939
Summary Branched-chain amino acids for hepatic encephalopathy
• No convincing evidence that branchedchain amino acids have a beneficial effect
on patients with hepatic encephalopathy
was identified.
The Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD001939
Is prophylactic antibiotics & SDD
needed ?
• Patients with FHF susceptibility to infections
# impaired phagocytic function
# reduced complement levels
# need for invasive procedures
• IV antibiotics : reduce infection 20%, BUT
not improve outcome or length of stay (A)
• No controlled studies for SDD, BUT Rolando
reported no additional benefit (A)
Does Lamivudine prevent FHF ?
• So far, no RCT support
• Bridging therapy for FHF to liver
transplantation
Benzodiazepine receptor antagonists
for hepatic encephalopathy ?
Benzodiazepine receptor antagonists
for hepatic encephalopathy ?
• Hepatic encephalopathy may be caused
by an activation of a receptor-complex in
the brain.
• Flumazenil, which inhibits this receptorcomplex, might ameliorate the symptoms.
Benzodiazepine receptor antagonists
for hepatic encephalopathy ?
• Thirteen randomised trials with 805 patients were
included. Eight trials used a crossover design. All trials
were double-blind
• Favourable prognosis [93%] survived in the flumazenil
group versus [92%] in the placebo group
• Flumazenil had a significant beneficial effect on
improvement of hepatic encephalopathy at the end of
treatment (RD 0.28; 95% CI 0.20 to 0.37, eight trials).
• Flumazenil had no significant effect on recovery (RD
0.13; 95% CI -0.09 to 0.36, two trials) or mortality RD
0.01; 95% CI -0.05 to 0.07, 10 trials).
• Flumazenil may be associated with adverse events
Benzodiazepine receptor antagonists
for hepatic encephalopathy ?
• Flumazenil leads to a short-term improvement of
hepatic encephalopathy in some patients with
chronic liver disease and a highly favourable
prognosis.
• No significant effect on recovery or survival
• Flumazenil may be considered for patients with
chronic liver disease and hepatic
encephalopathy, but cannot be recommended
for routine clinical use.
The Cochrane Database of Systematic Reviews 2005 Issue 1
Cerebral Edema in FHF
- Monitoring
• ICP monitor
# no controlled studies in FHF
• CT scan
# predicting power is poor
• Jugular vein saturation
# controlled trials needed
Cerebral Edema in FHF
- Treatment
• Osmotherapy
# mannitol 1g/Kg ( 0.5 g/Kg ) effective in FHF
( Canalese 1982 )
• Dexamethasone ineffective
• Barbiturate: no RCT
• Hyperventilation : no advantage in long term use
However, may try when unresponse to osmotics
What management for renal
failure in FHF ?
• Renal protecting agents
# So far, no proven protective agents for FHF
# Low dose dopamine  
• Renal replacement therapy
# has been a major part of routine management
# BUT no RCT proves renal replacement Tx
improve outcome
Artificial and bioartificial support
systems for liver failure
• Bridge' patients with acute or acute-on-chronic
liver failure to liver transplantation or recovery
• Twelve trials on artificial or bioartificial support
systems versus standard medical therapy (483
patients) and two trials comparing different
artificial support systems (105 patients) were
included
The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628
Artificial and bioartificial support
systems for liver failure
• Compared to standard medical therapy, support
systems had no significant effect on mortality
(RR 0.86; 95% CI 0.65-1.12) or bridging to liver
transplantation (RR 0.87; 95% CI 0.73-1.05)
• But a significant beneficial effect on hepatic
encephalopathy (RR 0.67; 95% CI 0.52-0.86)
The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628
Artificial and bioartificial support
systems for liver failure
• Effect of support systems depended on
 type of liver failure (P = 0.03).
In subgroup analyses, artificial support
systems appeared to reduce mortality by 33% in
acute-on-chronic liver failure (RR 0.67; 95% CI
0.51-0.90), but not in acute liver failure (RR 0.95;
95% CI 0.71-1.29) )
The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628
Artificial and bioartificial support
systems for liver failure
• Comparing artificial support systems
 significant mortality reductions with intermittent
versus continuous haemofiltration (RR 0.58; 95%
CI 0.36-0.94)
 no significant difference between five versus ten
hours of charcoal haemoperfusion (RR 1.03; 95%
CI 0.65-1.62).
 incidence of adverse events was inconsistently
reported
The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628
Summary
- Artificial and bioartificial support systems for liver failure
• Artificial support systems may reduce mortality
in acute-on-chronic liver failure.
• Artificial and bioartificial support systems did not
appear to affect mortality in acute liver failure.
• Strength of the evidence, additional RCTs are
needed before any support system can be
recommended for routine use.
The Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD003628
Thanks for your attention !