SEPSIS EN LA CIRROSIS HEPÁTICA - · PDF fileSEPSIS EN LA CIRROSIS HEPÁTICA J....

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J. Fernandez, unpublished data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.