TREATMENT OF ASCITES ANDSPONTANEOUS BACTERIAL PERITONITIS
Pere Ginès, MD
Liver Unit, Hospital ClínicBarcelona, Catalunya, Spain
FUNCTIONAL RENALABNORMALITIES IN CIRRHOSIS
AbnormalitySodium retentionWater retentionRenal vasoconstriction
Clinical consequenceAscites and edemaDilutional hyponatremiaHepatorenal syndrome
FUNCTIONAL RENALABNORMALITIES IN CIRRHOSIS
AbnormalitySodium retentionWater retentionRenal vasoconstriction
Clinical consequenceAscites and edemaDilutional hyponatremiaHepatorenal syndrome
DIURETICS
LARGE-VOLUMEPARACENTESIS
Increased tubular sodium reabsorption
ASCITESPathogenesis and therapeutic interventions
CIRRHOSIS
Reduced effective arterial blood volume
Portal hypertension
Stimulation of antinatriuretic/vasoconstrictor systems
Splanchnic arterial vasodilation
Sodium retention
ASCITES
LIVER TRANSPLANTATION
TIPS
CIRRHOSIS WITH ASCITES
Clinical types- Non-refractory
Moderate (grade 2)Large (grade 3)
- Refractory
Ginès et al., Gastroenterology 1987
MANAGEMENT OF LARGE ASCITESComparison of large-volume paracentesis plus albumin and diuretics
Efficacy (%) Side efffects (%)
P<0.05
P<0.05
Large-volumeparacentesis
+ albumin
HyponatremiaDiuretics Hepaticencephalopathy
00
20
60
100
10
20
30
80
40
Renalimpairment
Large-volume paracentesis + albuminDiuretics
LARGE-VOLUMEPARACENTESIS
Increased tubular sodium reabsorption
REFRACTORY ASCITESPathogenesis and therapeutic interventions
CIRRHOSIS
Reduced effective arterial blood volume
Portal hypertension
Stimulation of antinatriuretic/vasoconstrictor systems
Splanchnic arterial vasodilation
Sodium retention
ASCITES
LIVER TRANSPLANTATION
TIPS
DIURETICS
TIPS vs PARACENTESIS FOR REFRACTORY ASCITESSummary of studies
Hepatorenalsyndrome
Less frequentwith TIPS
-
Less frequentwith TIPS
-
-
Cost
-
-
Greaterwith TIPS
-
-
Survival
Betterwith TIPS
Nodifference
Nodifference
Betterwith TIPS?
Worsewith TIPS
Controlof ascites
Betterwith TIPS
Betterwith TIPS
Betterwith TIPS
Betterwith TIPS
Betterwith TIPS
Hepaticencephalopathy
Worsewith TIPS
Worsewith TIPS
Worsewith TIPS
Nodifference
Nodifference
Salerno et al.,Hepatology 2005
Sanyal et al.,Gastroenterology 2003
Ginès et al.,Gastroenterology 2002
Rossle et al.,N Engl J Med 2000
Lebrec et al.,J Hepatol 1997
REFRACTORY ASCITESTreatment strategy
Initial therapy- Total paracentesis plus i.v. albumin (8 g/L of ascites)- Partial paracentesis (<5 L) with artificial plasmaexpanders if albumin is not available
- Consider liver transplantation
Maintenance therapy- Repeated paracentesis plus i.v. albumin
when necessary- TIPS is not the treatment of choice. Better control ofascites should be weighed against increased riskof severe encephalopathy and higher costs
ASCITES / DILUTIONAL HYPONATREMIAPathogenesis and therapeutic interventions
CIRRHOSIS
Reduced effective arterial blood volume
Portal hypertension
Stimulation of vasoconstrictor systems
Splanchnic arterial vasodilation
ASCITES DILUTIONAL HYPONATREMIA
Vasopressin V2 receptor
Solute-free water retention
Aldosterone receptor
Sodium retention
Spironolactone V2 receptorantagonists
Renin-aldosteronesystem
Antidiuretic hormone(vasopressin)
- Double-blind, randomized, parallel group comparisonof fixed doses of Satavaptan with placebo
V2 RECEPTOR ANTAGONISTS IN CIRRHOSISWITH ASCITES AND HYPONATREMIA
Placebo
Satavaptan 5 mg/day
Satavaptan 12.5 mg/day
Satavaptan 25 mg/day
Spironolactone 100 mg/day
Screeningperiod
7 days 14 days
Treatment period Post-treatmentfollow-up
7 days
Ginès et al., EASL 2006
V2 RECEPTOR ANTAGONISTS IN CIRRHOSISWITH ASCITES AND HYPONATREMIA
Serum sodium (mmol/L)Body weight (Kg)
SPONTANEOUS BACTERIAL PERITONITIS
Key findings- Wide clinical spectrum: from asymptomatic casesto septic shock
- Diagnosis based on increased neutrophil count in ascitic fluid- High resolution rate with third-generation cephalosporins- High hospital mortality (10-20%)- Poor long-term outcome
Important clinical issues- Hepatorenal syndrome common, even after infection resolution- Adrenal insufficiency frequently associated- Prevention in high risk patients
SPONTANEOUS BACTERIAL PERITONITIS
Key findings- Wide clinical spectrum: from asymptomatic casesto septic shock
- Diagnosis based on increased neutrophil count in ascitic fluid- High resolution rate with third-generation cephalosporins- High hospital mortality (10-20%)- Poor long-term outcome
Important clinical issues- Hepatorenal syndrome common, even after infection resolution- Adrenal insufficiency frequently associated- Prevention in high risk patients
SBP-INDUCED CIRCULATORY AND RENAL FAILUREProposed mechanism
SPONTANEOUS BACTERIAL PERITONITIS
Arterial vasodilation(cytokines, NO, CO)
IMPAIRMENT OF EFFECTIVE ARTERIAL BLOOD VOLUME
ACTIVATION OF VASOCONSTRICTOR SYSTEMS
REDUCED RENAL PERFUSION
HEPATORENALSYNDROME
DECREASED SURVIVAL
Albumin+
Sort et al., N Engl J Med 1999
SPONTANEOUS BACTERIAL PERITONITISEffects of plasma volume expansion with albumin
Hepatorenal syndrome (%) Mortality (%)
p=0.02 p=0.01
Cefotaxime CefotaximeCefotaxime+ albumin
Cefotaxime+ albumin
00
10
20
30
10
20
30
SPONTANEOUS BACTERIAL PERITONITIS
Key findings- Wide clinical spectrum: from asymptomatic casesto septic shock
- Diagnosis based on increased neutrophil count in ascitic fluid- High resolution rate with third-generation cephalosporins- High hospital mortality (10-20%)- Poor long-term outcome
Important clinical issues- Hepatorenal syndrome common, even after infection resolution- Adrenal insufficiency frequently associated- Prevention in high risk patients
ADRENAL INSUFFICIENCY AND SEPSIS IN CIRRHOSIS
Tsai et al., Hepatology 2006
Adrenal insufficiencyand outcome (%)
80
60
40
20
0
No adrenal insufficiencyAdrenal insufficiency
Hemodynamicunstability
Renalfailure Mortality
79%
35%
73%
24%
37%
81%
Fernández et al., Hepatology (in press)
Septic shock: survival according totreatment of adrenal insufficiency
0Days
30 45 6015
1.0
0.4
0.0
Pro
babi
lity
0.8
0.6
0.2
Treatment (n=25)
p=0.003 No treatment (n=50)
SPONTANEOUS BACTERIAL PERITONITIS
Key findings- Wide clinical spectrum: from asymptomatic casesto septic shock
- Diagnosis based on increased neutrophil count in ascitic fluid- High resolution rate with third-generation cephalosporins- High hospital mortality (10-20%)- Poor long-term outcome
Important clinical issues- Hepatorenal syndrome common, even after infection resolution- Adrenal insufficiency frequently associated- Prevention in high risk patients
SELECTIVEINTESTINALDECONTAMINATION
Intestinal bacterial overgrowthImpaired intestinal motilityImpaired intestinal barrier
SPONTANEOUS BACTERIAL PERITONITISPathogenesis and prophylactic interventions
CIRRHOSIS
Spontaneous bacteremia
Sinusoidal portal hypertension
Colonization of ascitic fluid
Bacterial translocation to lymph nodes
SPONTANEOUS BACTERIAL PERITONITIS
Reduced activity of the reticuloendothelialsystem (severe liver failure)
Reduced antibacterial activityof the ascitic fluid (low-protein ascites)
Placebo
p=0.0013
Norfloxacin
SBP caused by aerobicGram-negative bacteria
0Months
8 12 204 16
1.0
0.4
0.0
Pro
babi
lity
0.8
0.6
0.2Norfloxacin
p=0.0063
Placebo
Total
0Months
8 12 204 16
EFFECT OF LONG-TERM NORFLOXACIN ADMINISTRATIONIN SBP RECURRENCE IN CIRRHOSIS
Ginès et al, Hepatology 1990
SELECTIVE DECONTAMINATION IN CIRRHOSISEFFECT ON RENAL FUNCTION AND SURVIVAL
Fernández et al., unpublished
Pro
babi
lity
Days0 100 300 400
1.0
0.6
0.4
0.2
0.0
0.8
Survival
1.0
0.6
0.4
0.2
0.8
Placebo
Norfloxacin
p=0.02
Pro
babi
lity
Days0 100 300200
0.0
Hepatorenal syndrome
400
Norfloxacin
Placebo
p=0.05
200
Patients without previous SBP with advanced liver failure and low protein ascites
ACKNOWLEDGEMENT
C. AlessandriaR. BatallerME. BaccaroS. BadalamentiI. BucknanB. CalahorraA. CárdenasR. CelaG. Fernández-EsparrachA. GinèsM. GuevaraW. JiménezJ. Llach
M. Martín-LlahíR. OrtegaO. OzdoganMN. PépinR. PlanasT. RestucciaJ. SalóJM. SalmerónP. SortC. TerraLl. TitóA. TorreJ. Uriz