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