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SEPSIS EN LA CIRROSIS HEPÁTICA
J. FernándezLiver ICU, Hospital Clínic Barcelona
Conferència d'experts de la SOCMIC, Barcelona, 28 de gener 2010
Index
Diagnosis and antibiotic treatment of bacterial infections in cirrhosis.
Plasma volume expansion in the treatment of SBP and non-SBP infections.
Relative adrenal insufficiency in cirrhotic patients with septic shock.
Incidence of bacterial infections in liver cirrhosis
Patients with infection 33-46
Spontaneous bacterial peritonitis 7-23Urinary tract infection 18-29Pneumonia 6-9 Bacteremia 4-6Other infections 3-6
Range (%)
Type of infection
0
20
40
60
80
100
120
140 SBP
Urinary infection
Pneumonia
Secondary bacteremia
Cellulitis
SpontaneousbacteremiaCholangitis
Secondary peritonitis
n
Fernández et al. Hepatology 2002
n= 572
Type of bacteria
0
20
40
60
80
100
1981-1990 1998-2000 2005-2007
% Gram-negativebacilli
Gram-positivecocci
Fernández et al. Hepatology 2002, Acevedo et al J. Hepatol 2009
Site of infection and causative organisms
0
20
40
60
80
Community-acquired Nosocomial
% Gram-negativebacilliGram-positivecocciBoth
Fernández et al. Hepatology 2002
p=0.0001
Degree of instrumentation and causative organisms
0
20
40
60
80
Invasive procedures orICU admission
No
% Gram-negativebacilliGram-positivecocciBoth
Fernández et al. Hepatology 2002
p=0.0001
SIRS criteria and infection diagnosis in cirrhosis
0
20
40
60
80
100
Non infected Infected
%
SIRS
No SIRS
J. Fernandez, unpublished data
n= 233
p=0.04
C-reactive protein and white blood cell count in E. coli bacteremia in cirrhosis
0
5
10
15
20
Cirrhosis No liver disease
C-reactiveprotein (mg/dl)WBC (x10 /L)9
Park et al. Diagnostic Microbiology and Infectious Disease 2005
p < 0.001
C-reactive protein in E. colibacteremia
Park et al. Diagnostic Microbiology and Infectious Disease 2005
0
5
10
15
20
25
30
35
40
45
p < 0.001
Infected/No cirrhosis
Infected/Cirrhosis C-P B
Infected/Cirrhosis C-P C
Non-infected/ cirrhosis
C-r
eact
ive
prot
ein
(mg/
dl)
Procalcitonin and infection diagnosis in cirrhosis
Decompensated cirrhosis
With infection 2.8 ng/ml 0.4-20.4 ng/ml
Without infection 0.6 ng/ml 0.1-5.9 ng/ml
Non-decompensated cirrhosis 0.4 ng/ml 0.1-1.2 ng/ml
Median Range
Levels > 0.58 ng/ml had a sensitivity of 92% and specificity of 78% for the diagnosis of infection?
Connert et al. Z Gastroenterol 2003
Spontaneous bacterial peritonitis
Definition: infection of the ascitic fluid in the absence of a localsource of infection.
Clinical data: Asymptomatic patients or different symptoms:fever, abdominal pain, vomiting, diarrhea, renal impairment,hepatic encephalopathy, gastrointestinal bleeding.
Diagnosis: Always performed by paracentesis (polymorphonuclearcell count in ascitic fluid ≥ 250/mm3).
Causative organisms: 80% enterobacteriaceas (aerobic gram-negative bacilli), 20% bacteria of extraintestinal origen (non-enterococcal streptococci).
Empirical treatment: third-generation cephalosporins oramoxicillin+ clavulanic acid.
Reagent strips in the diagnosis of SBP
Sapey et al(n=127)
Nousbaum et al(n=1041)
Campillo et al(n=116)
88-100%65-85%
45%
70%80%
Sensitivity
92-100%96-100%
99%
95%90%
Specificity
75-94%
78%
64%52%
PPV
Multistix
Multistix
Nephur
Multistix
Combur
Nguyen-Khac et al. Aliment Pharmacol Ther 2008
83-92%
SBP resolution and hospital survival
0
20
40
60
80
100
1971-1980 1981-1990 1991-2000
% ResolutionSurvival
Antibiotic treatment in SBP
Cefotaxime 95% 70-90%
Ceftriaxone 90-95% 70-90%
Ceftizoxime 87% 84%
Cefonicid 94% 63%
Amoxicillin +clavulanic acid 85-95% 63-80%
Oral ofloxacin 80% 80%
SBP resolution Hospital survival
0
20
40
60
80
100
No SID (n=135) SID (n=37)
Quinolone-resistant
Trimethoprim-s-resistant
Cephalosporins-resistant
Long-term quinolone prophylaxis and antibiotic susceptibility of total isolated GNB
%
p=0.0002
Fernández et al. Hepatology 2002
p=0.02
0
20
40
60
80
100
No SID (n=29) SID (n=14)
Quinolone-r
Trimethoprim-s-r
Cephalosporins-r
Long-term quinolone prophylaxis and antibiotic susceptibility of GNB isolated in SBP
%
p=0.04
Fernández et al. Hepatology 2002
Treatment of non-SBP infections
Urinary infections:Third-generation cephalosporins or amoxicillin+ clavulanic acid. At present, quinolones o trimethoprim-sulphametoxazol are not recommended in our area.Add ampicillin if urinary catheterization.
Pneumonia:Treatment as in the general population. Risk factors for aspirative pneumonia: balloon tamponade, severe hepatic encephalopathy, massive gastrointestinal bleeding.
Spontaneous bacteremia:Third-generation cephalosporins or amoxicillin+clavulanic acid.
Cellulitis:Third-generation cephalosporins+cloxacillin or amoxicillin+clavulanic acid.
Non-SBP infections
Transcatheter arterial embolization (hepatocellular carcinoma):No antibiotic prophylaxis. Therapy in the case of sepsis with amoxicillin+ clavulanic acid.
Transjugular intrahepatic portosystemic shunt (TIPS):Antibiotic prophylaxis during insertion (antipseudomonal cephalosporin plus vancomycin).
Variceal esclerotherapy, banding or PEI:No antibiotic prophylaxis.
Type and origin of infection
Type of infection All infections Nosocomial
SBP 126 (25%) 32(25%)
UTI 96 (19%) 42 (44%)
Cellulitis 66 (13%) 11 (17%)
Pneumonia 44 (9%) 26 (59%)
Others 168 (34%) 62 (37%)
Total 500 (100%) 173 (34%)
* 224 patients **SBP: Spontaneous bacterial peritonitis, UTI: Urinary tract infection
Acevedo et al. J Hepatol 2009
Recommended empirical antibiotic therapy
Ceftazidime + CiprofloxacinNosocomial Pneumonia
Ceftriaxone + Cloxacillin or Amoxicillin‐Clavulanic AcidCellulitis
CeftriaxoneUTI
Ceftriaxone + Macrolide or Clindamycin or LevofloxacinCommunity‐acquired pneumonia
Type of infection Type of empirical antibiotic therapy
SBP Ceftriaxone
SBP: Spontaneous bacterial peritonitis, UTI: Urinary tract infection
Acevedo et al. J Hepatol 2009
Efficacy of empirical antibiotic therapy
Infections treated with empirical
therapy
Response to empirical therapy
All infections Community-acquired Nosocomial
SBP (n=107) 72 (67%) 67 (76%) 5 (26%)
UTI (n=89) 48 (54%) 36 (71%) 12 (32%)
Pneumonia (n=28) 10 (36%) 7 (64%) 3 (18%)
Cellulitis (n=54) 43 (80%) 40 (83%) 3 (50%)
Others (n=136) 97 (71%) 74 (84%) 23 (48%)
TOTAL (n=414) 271 (65%) 224 (78%) 43 (36%)
p<0.001
p=0.09
p=0.02
p<0.001
p<0.001
p=0.001
Acevedo et al. J Hepatol 2009
Type of isolated bacteria
All InfectionsCommunity‐acquired
Nosocomial
Culture positive 269 (54%) 145 (44%) 124 (72%)
Gram‐negative bacilli
132 (49%) 90 (62%) 69 (55%)
Gram‐positive cocci
128 (48%) 64 (44%) 64 (52%)
Acevedo et al. J Hepatol 2009
Multiresistant bacteria
Acevedo et al. J Hepatol 2009
1 (1%) Acinetobacter spp.
1 (1%) Achromobacter spp.
1 (1%) Citrobacter freundii
3 (3%) Stenotrophomona maltophilia
14 (15%) Methicillin resistant S. aureus
16 (17%) P. aeruginosa
14 (15%) Enterococcus faecium
Type of MR bacteria Number of cases (%)
ESBL enterobacteria 43 (46%)
Isolated in 59 patients (26%)
Prevalence of multiresistant bacteria
Type of infection All infections Community-acquired Nosocomial
SBP 10 (8%) 3 (3%) 7 (22%)
UTI 38 (40%) 13 (24%) 25 (60%)
Cellulitis 7 (11%) 4 (7%) 3 (27%)
Pneumonia 11 (25%) 2 (11%) 9 (35%)
Others 25 (15%) 6 (6%) 19 (31%)
TOTAL 91 (18%) 28 (9%) 63 (36%)
p=0.001
p=0.003
p=0.08
p=ns
p<0.001
p<0.001
Acevedo et al. J Hepatol 2009
Global resolution of the infection
Type of infection All infections
Community-acquired Nosocomial
Number of cases 500 327 173
Resolution of infection 441 (88%) 311 (95%) 130 (76%)
p<0.001
Acevedo et al. J Hepatol 2009
Clinical outcome according to causative bacteria (multiresistant or not)
24%
30%
10%10%
0
10
20
30
40
50
Septic shock Mortality
MR bacteria Not MR bacteria
p<0.001 p=0.001
%
Acevedo et al. J Hepatol 2009
1%8%
43%
0
20
40
60
Prevalence of ESBL infections
0 Risk factor 1 Risk factor 2 Risk factors
Risk factors for community-acquired ESBL enterobacterial infections
%
p<0.001
Selective intestinal decontamination: OR:3 (95%CI:1.4-7.8)
Acevedo et al. J Hepatol 2009
ESBL Infection within the last 6 months: OR:6 (95%CI:2-18)
Risk factors for nosocomial ESBL enterobacterial infections
1%
21%
39%
0
20
40
Prevalence of ESBL infections
0 Risk factors 1 Risk factor 2-3 Risk factors
p<0.001%
Selective intestinal decontamination: OR:4 (95%CI:1.5‐11)
Recent (1 month) hospital admission: OR:4.4 (95%CI:1.5‐11)
β‐lactamic antibiotics in the same hospitalization: OR:5 (95%CI:1.4‐18)
Acevedo et al. J Hepatol 2009
SBP caused by extended-spectrum and AmpC B-lactamase producing enterobacteria
Author Country Prevalence of ESBL*
Prognosis Risk factors
Dupeyron et al , 1998 France 22% No data Previous exposition to quinolones or B-lactams
Fernandez et al, 2002 Spain 5% No data No data
Park et al , 2003 Korea 7% in 1995 28% in 1999
Hospital mortality: 94% Risk factor for mortality
Previous exposition to quinolones or B-lactams Current or recent hospitalization
Cereto et al , 2007 Spain 6% (13% in patients on norfloxacin prophylaxis)
No data Norfloxacin prophylaxis
Angeloni et al , 2008 Italy 40% No data Health-care related infections
Cheong et al , 2009 Korea 41% in nosocomial SBP 10% in community episodes
30-day mortality: 48% Risk factor for mortality
Previous exposition to B-lactams Hospitalization
Yakar et al , 2009 Turkey 15% No data No data
Umgelter et al , 2009 Germany 0% No data No data
Song et al , 2009
Korea 7.5% Higher 30-day mortality Hospitalization Previous exposition to antibiotics Previous history of SBP
Conclusions
• Infections by multiresistant bacteria are frequent in patients with cirrhosis.
• The traditional recommended empirical antibiotic therapy is not effective in a high proportion of patients.
• Predictors of multiresistant bacteria in community-acquired infection are: selective intestinal decontamination and previous ESBL enterobacteria infection.
• Predictors of multiresistant bacteria in nosocomial infection are: selective intestinal decontamination, recent hospitalization and prior treatment with β-lactam antibiotics.
Effects of plasma volume expansionwith albumin in SBP
30
20
10
0
Mortality (%)
Cefotaxime+ albumin
0
30
20
10
Hepatorenal Syndrome (%)
p=0.02
Cefotaxime Cefotaxime+ albumin
Cefotaxime
p=0.01
Sort et al. N Engl J Med 1999
Effects of hydroxyethyl starch (HES) or albumin (ALB) administration on central volume
RAP (mmHg)
ANP (fmol/mL)
PCP (mmHg)
8±27±3
55±2145±32
10±411±3
Baseline
9±27±3
85±3728±18
11±514±4
Resolution
0.03ns
0.05ns
ns0.03
p
HES
HES
HES
ALB
ALB
ALB
Fernández et al. Hepatology 2005
MAP (mmHg)
PRA (ng.mL/h)
76±980±15
5.7±4.78.5±7.3
Baseline
85±1381±8
3.1±3.416.8±24.6
Resolution
0.01ns
0.04ns
p
HES
HES
ALB
ALB
Fernández et al. Hepatology 2005
Effects of hydroxyethyl starch or albumin administration on effective arterial volume
Effects of plasma volume expansionwith albumin in SBP. Patients at risk
Cefotaxime Cefotaxime+ albumin
TOTAL 18/63 (28.6%) 6/63 (9.5%)
BUN <30 - BIL >4 5/15 (33%) 0/16 (0%)
BUN <30 - BIL <4 0/20 (0%) 0/24 (0%)
BUN >30 - BIL <4 3/15 (20%)5/14 (35.7%)
BUN >30 - BIL >4 3/8 (37.5%)8/14 (57%)
Sort et al. N Engl J Med 1999
Effects of plasma volume expansionwith albumin in non-SBP
30
20
10
0
3-months mortality (%)
Antibiotics+ albumin
(n=56)
0
30
20
10
Hepatorenal Syndrome (%)
p=ns
Antibiotics(n=54)
Antibiotics+ albumin
(n=56)
Antibiotics(n=54)
p=ns
Nazar et al. J Hepatol 2009
RAI in Critically Ill Patients with Liver Failure
Number Type of critical Incidenceof patients illness
Harry et al (2002) 45 Acute liver failure 62%
Harry et al (2003) 20 Acute or chronic 69%liver failure andseptic shock
Marik et al (2005) 24 Acute liver 33%failure
147 Chronic liver 66%disease
Tsai et al (2006) 101 Cirrhosis and 51%severe sepsis
Fernandez et al (2006) 25 Cirrhosis and 68%septic shock
Thierry et al (2007) 14 Cirrhosis and 77%septic shock
Cheyron et al (2008) 50 Cirrhosis 62%
Incidence of Adrenal Insufficiency in Severe Sepsis and Septic Shock in Cirrhosis
Tsai et al. Hepatology 2006
25
50
75
0
100
Severesepsis
Septicshock
p<0.001
%
Renal, Hepatic and Adrenal Function in Severe Sepsis and Septic Shock in Cirrhosis
Tsai et al. Hepatology 2006
25
50 50
25
75
0
RENAL FAILURE (%)
100
Adrenalinsufficiency
Normalfunction
CHILD-PUGH CLASS C (%)
0
100
75
Adrenalinsufficiency
Normalfunction
p=0.01
p<0.001
Adrenal Insufficiency and Outcome in SevereSepsis and Septic Shock in Cirrhosis
Tsai et al. Hepatology 2006
25
50 50
25
75
0
ICU MORTALITY (%)
100
Adrenalinsufficiency
Normalfunction
HOSPITAL MORTALITY (%)
0
100
75
Adrenalinsufficiency
Normalfunction
p<0.001p<0.001
Resolution of septic shock, hospital and ICU mortality
75 PATIENTS WITH CIRRHOSIS AND SEPTIC SHOCK
GROUP 1 (n=25)Prospective series
Evaluation of adrenal function Hydrocortisone 50mg/6h IV
GROUP 2 (n=50) Retrospective series
No evaluation of adrenal function
Adrenal insufficiency in septic shock in cirrhosis. Effects of hydrocortisone on survival
Fernández et al. Hepatology 2006
Prevalence of RAI and liver function
0
20
40
60
80
Child-Pugh C Child-Pugh A-B
p=0.08
* Prevalence in the study population: 68% Fernández et al. Hepatology 2006
%
Effects of low-dose steroid administration on the resolution of septic shock in cirrhosis
0
20
40
60
80
100
Prospective series Retrospective series
p=0.001
Fernández et al. Hepatology 2006
%
(n=25) (n=50)
ICU and Hospital Survival
0
20
40
60
80
Prospective series Retrospective series
ICU survival
Hospital survival
**p= 0.003
Fernández et al. Hepatology 2006
* p= 0.03
* **
%
Sprung C et al. N Engl J Med 2008;358:111-124
Corticus StudyKaplan-Meier Curves for Survival at 28 days
Sprung C et al. N Engl J Med 2008;358:111-124
Corticus StudyKaplan-Meier Curves for Shock Reversal
Conclusions
Relative adrenal insufficiency is very frequent in patients with advanced cirrhosis and septic shock.
Treatment with low doses of hydrocortisone seems to be associated with a marked increase in shock reversal and hospital survival.
These positive effects of steroids on cirrhotic patients with septic shock should be confirmed in RCT.