ASCITESDr. Hary Bagijo Sp.PDSeksi Hepatology-GastroenterologyFK UHT/RSAL Dr.Ramelan

ASCITESDEFINITION FREE FLUID IN THE ABDOMINAL CAVITYJAMA 1992;267:2645-2648

Ascitesascites accumulation of fluid in the abdominal cavity

Whats so bad about ascites?PainfulAnorexia & malnutritionReduced mobility with deconditioningHerniasImpaired ventilation with atelectasis & pneumoniaIncreased variceal pressureMay become infected (SBP)

Causes of ascitesCirrhosisHepatic congestion (CHF)Renal diseasePancreaticMalignancyInfections (TB)Inflammatory diseaseHypothyroidism

Why do cirrhotics retain salt and water?UnderfillLow albumin & portal HTNTransudation of fluidReduced renal perfusionRenin releaseSalt retention

Why do cirrhotics retain salt and water?Overflow

Systemic vasodilatationReduced renal perfusionRenin, angiotensin system activationSalt retentionIncreased venous pressurePortalSystemicTransudation of fluid

Features of the systemic hemodynamic derangement of cirrhosisSystemic vasodilatation Low blood pressureHigh cardiac outputMesenteric vasodilatation Portal hypertensionPulmonary vasodilatationHepatopulmonary syndromeRenal vasodilatationReduced GFR

Stages of ascitesSalt avidity without ascitesOvert edema/ascitesResponsive to diuretics/salt restrictionRefractoryHepatorenal syndromeType IIType I

Medical RxSalt restrictionDistal tubular diureticsSpironolactoneAmilorideLoop and proximal diureticsFurosemide

Resistant ascitesInadequate treatmentPatient noncompliancePhysician reluctanceRefractory ascitesFailure to resolve despite maximal diureticsIntolerance to treatmentDiuretic side effects (cramps, etc.)HyponatremiaPrerenal azotemiaHepatorenal syndrome, type IIRefractory ascites with persistent Cr > 1.5

PATHOPHYSIOLOGY OF ASCITES HYDROSTATIC PRESSURECIRRHOSISCHFCONSTRICTIVE PERICARDITIS OSMOTIC PRESSURE NEPHROTIC SYNDROMEMALNUTRITIONPROTEIN LOSING ENTEROPATHYFLUID PRODUCTION EXCEEDING RESORPTIVE CAPACITYINFECTION TBMALIGNANCYJAMA 1992;267:2645-2648

HISTORY

H/O INCREASED ABDOMINAL GIRTHH/O PEDAL EDEMAH/O WEIGHT GAIN H/O CHFH/O HEPATITIS H/O ETOHH/O MALIGNANCY

JAMA 1992;267:2645-2648USEFULNOT AS USEFUL

BULGING FLANKSJAMA 1992;267:2645-2648ASCITES OR OBESITY?

SHIFTING DULLNESSMETHOD OF EXAMINATIONBEGIN BY PERCUSSING AT THE UMBILICUS AND MOVING TOWARD THE FLANKS. THE TRANSITION FROM AIR TO FLUID CAN BE IDENTIFIED WHEN THE PERCUSSION NOTE CHANGES FROM TYMPANIC TO DULL. ROLL THE PATIENT ON THEIR SIDE AND PERCUSS AS BEFORE. THE AREA OF TYMPANY WILL SHIFT TOWARDS THE TOP AND THE AREA OF DULLNESS TOWARDS THE BOTTOM.JAMA 1992;267:2645-2648

SHIFTING DULLNESSMETHOD OF EXAMINATIONHAVE THE PATIENT OR ASSISTANT PLACE THEIR HANDS IN THE MIDLINETAP ONE FLANK SHARPLY AND USE THE FINGERTIPS OF THE OPPOSITE HAND TO FEEL FOR AN IMPULSE ON THE OPPOSITE FLANKJAMA 1992;267:2645-2648TAPFEELPATIENT OR ASSISTANT

PUDDLE SIGNMETHOD OF EXAMINATIONPATIENT IS PRONE FOR 3-5 MINUTES AND THEN RISES TO ALL FOURSDIAPHRAGM OF THE STETHOSCOPE IS PLACED OVER MOST DEPENDENT AREA OF THE ABDOMENBEGIN BY FLICKING A FINGER OVER A LOCALIZED FLANK AREA MOVE THE STETHOSCOPE OVER THE OPPOSITE FLANKSUDDEN INCREASE IN INTENSITY IS A POSITIVE SIGN (NO LONGER USED)JAMA 1992;267:2645-2648

Causes of ascitesHepatic (cirrhosis, fibrosis, obstruction)Renal (nephrotic syndrome, obstrutive, PD)Cardiac (heart failure, constrictive pericarditis)Infectious (abscess,TB, Chlamydia, schistosomia)Gastraointestinal (infarcted bowel perforation)Neoplastic (lymphoma, neuroblastoma)Pancreatic (pancreatitis, ruptured pancreatic duct)GYN (ovarian tumor, torsion, rupture)Miscellaneous (SLE, VP shunt, chylous, hypothyroidism)

Physical diagnosisBulging flanksFlank dullnessShifting dullnessFluid wavePedal edemaPuddle sign

Pathophysiologic mechanisms

Initial therapySodium restrictionDiureticsSpironolactone 50 400 mg po QDFurosemide 40 160 mg po BID

Initial therapyGoal weight loss per dayNo edema: 500 gramsEdema: up to 1 kg

Human Serum Albumin: Properties and Physiological Function

Human Serum Albumin: A Unique ProteinMost abundant protein in blood plasma (accounting for approximately 60% of all plasma proteins)Multifunctional proteinPossesses:unique ligand-binding capacityenzymatic propertiesdifferent types of hydrolytic activityServes as a: transporterstorehouse for several endogenous and exogenous compoundsKragh-Hansen U, et al. Biol Pharm Bull. 2002;25:695-705; Peters T Jr. San Diego: Academic Press; 1996.

Human Serum Albumin: StructureAlbumin is a heart-shaped protein with three spherical domains (I-III), each of which is comprised of 2 subdomains (A and B)Kragh-Hansen U, et al. Biol Pharm Bull. 2002;25:695-705.

Human Serum Albumin: StructureHuman serum albumin (HSA) is: A single-chain proteinA simple protein, thus lacking prosthetic groups and covalently bound carbohydrate and lipidSynthesized and secreted from the liverContains 585 amino acidsMolecular mass: 66,500 DaKragh-Hansen U, et al. Biol Pharm Bull. 2002;25:695-705; Peters T Jr. San Diego: Academic Press; 1996.

Human Serum Albumin: Physiological FunctionMaintains oncotic pressure difference between plasma and interstitial spaceInvolved in the regulation of fluid exchange across the capillary wallsEnsures distribution of body fluids between intravascular compartments and body tissuesNegatively charged (overall charge: -15) The glomerular basement membrane, which is also negatively charged, cannot filtrate albumin in urine

Gekle M. Annu Rev Physiol. 20052;67:12-1=12.22.

Human Serum Albumin: Physiological FunctionServes as a transporter of a variety of substances, such asCa2+ Thyroid and other hormonesUnconjugated bilirubinFatty acidsMagnesiumTrytophanDrugsToxinsToxins are transported to the liver where they are converted to a water-soluble form that can be excretedGekle M. Annu Rev Physiol. 20052;67:12-1=12.22.

Human Serum Albumin: Physiological FunctionTransport properties of albumin are dependent on:Its ability to competitively absorb metabolites at the loading stageCapacity of the binding siteStrength of ligand fixation during transfer in bloodRate of albumin-ligand complex dissociation, which occurs during interaction with target objectsMedInnovation GmbH. 2004. Available at: http://www.medinnovation.de/background/hsa.htm.

Human Serum Albumin: Physiological FunctionProperties that allow the many functions of albumin:Flexibility of the protein molecule to change conformationReadiness/flexibility for chemical/biological change at binding sitesMedInnovation GmbH. 2004. Available at: http://www.medinnovation.de/background/hsa.htm.

Human Serum Albumin: Physiological FunctionBuffers pHInfluences renal elimination of bound small-molecular substances Binding of these substances to albumin decreases their filtration rate

Human Serum Albumin: Normal ValuesAlthough the normal value of human serum albumin depends on the laboratory, a level of 3.5 g/dL to 5 g/dL is generally considered to be normal

Human Serum Albumin: Transport MalfunctionsSeveral factors can modify the conformation/properties of albuminModification of the human serum molecule may be involved in several disease statesSolid tumors preferentially accumulate human serum albumin Such modification of the human serum albumin molecule may have an effect on organ function and/or disease progression

Human Serum Albumin: What Causes Low levels of Albumin?Albumin deficiency may be caused by:Cirrhosis of the liver (diseased liver is unable to produce adequate albumin)Excess excretion by kidneys/bowel (eg, nephrotic syndrome and protein-losing enteropathy, respectively)Shock/trauma (loss of albumin from circulation)Damaged capillaries and blood vessels, which permit leakage of albumin from the vascular system (eg, severe burns)Malnutrition (or very low-protein diet)Malabsorption syndromes (eg, Crohns disease, sprue, Whipples disease)

Adverse Effects of Low Human Serum AlbuminLoss of oncotic pressure, resulting in leakage of fluid from the blood vessels into tissues:Swelling in the ankles (edema)Fluid accumulation in the abdomen (ascites)Fluid accumulation in the lungs (pulmonary edema)Breakdown of the transport system

Reversing Low Albumin Levels: IndicationsEmergency treatment of hypovolemic shockBurn therapy (during the first 24 hours to restore volume; beyond 24 hours to maintain oncotic pressure)Cardiopulmonary bypass (priming)Acute liver failureSequestration of protein-rich fluids (eg, acute peritonitis, pancreatitis, mediastinitis, extensive cellulitis)Hypoproteinemia, with or without edema (eg, post-surgery, sepsis, ICU patients)Bayer Corporation, Pharmaceutical Division. Elkhart, IN; February 2002.

Reversing Low Albumin Levels: Indications (contd)Adult respiratory distress syndrome (ARDS)Neonatal hemolytic diseaseErythrocyte resuspension (to avoid excessive hypoproteinemia during certain types of exchange transfusion or with the use of very large volumes of previously frozen or washed red blood cells)Acute nephrosisRenal dialysisBayer Corporation, Pharmaceutical Division. Elkhart, IN; February 2002.

Hemodynamic Effects of a 40-g IV Albumin Infusion in Patients with CirrhosisIncreased plasma volumeDecreased systemic vascular resistanceDecreased arterial complianceDecreased plasma renin and aldosterone

Brinch et al: J Hepatology. 2003;39:24-31.

Albumin in Liver DiseasesPrevalence of liver diseaseOverview of portal hypertensionUses of AlbuminResuscitationAscitesHepatorenal syndromeSpontaneous Bacterial Peritonitis

Albumin in Liver DiseasesPrevalence of liver diseaseOverview of portal hypertensionUses of albuminResuscitationAscitesHepatorenal syndromeSpontaneous bacterial peritonitis

Progression of FibrosisNo FibrosisStage 1: Fibrous expansion of some portal areasStage 3: Fibrous expansion of most portal areas with occasional portal to portal bridging Stage 4: Fibrous expansion of portal areas with marked bridging (portal to portal and portal to central) Stage 5,6: Cirrhosis, probable or definedCirrhotic liver: Gross anatomy of cadaverCourtesy of Gregory Everson, MD.Liver injury (ie, hepatitis C, hepatitis B, alcohol)

Portal HypertensionPortal hypertensionCirrhosisIncreased intrahepatic vascular resistanceDecreased nitric oxidePortal hypertensionHyperdynamic circulationIncreased splanchnic blood flowIncreased total blood volumeIncreased cardiac outputSystemic vasodilation (decreased systemic vascular resistance)Increased renin-angiotensin, vasopressin, sympathetic systems

Albumin in Liver DiseasesPrevalence of liver diseaseOverview of portal hypertensionUses of albuminResuscitationAscitesHepatorenal syndromeSpontaneous bacterial peritonitis

Albumin in Liver DiseasesPrevalence of liver diseaseOverview of portal hypertensionUses of albuminResuscitationAscitesHepatorenal syndromeSpontaneous bacterial peritonitis

Pathophysiology of Ascites

AscitesSecond most frequent complication of cirrhosis5-year cumulative rate: 30%Once ascites develops the 1-year survival is about 50%Removal of large amounts of ascitic fluid (>2 liters) should be with concomitant albuminPrevents circulatory dysfunction (CD)CD is associated with rapid reaccumulation of ascitesCD has an increased mortalityGastroenterology. 1997;113:579.

Hemodynamic Effects of Albumin in Patients with Cirrhosis40-g IV albumin infusion in patients with cirrhosis produces: h Plasma volumei Systemic vascular resistancei Arterial compliancei Plasma renin and aldosteroneJ Hepatology. 2003;39:24-31.

Treatment of Moderate-Large AscitesInitialLarge-volume paracentesis + IV albumin (8 g/L removed)MaintenanceLow-sodium dietSpironolactone + loop diuretics (furosemide)Large-volume paracentesis + albuminAmerican Association for the Study of Liver Disease. 2004.

Albumin in Liver DiseasesPrevalence of liver diseaseOverview of portal hypertensionUses of albuminResuscitationAscitesHepatorenal syndrome (HRS)Spontaneous bacterial peritonitis (SBP)

Hepatorenal Syndrome (HRS)End-stage spectrum of ascites; represents the extreme in systemic vasodilationDecrease in effective blood volumeMaximal activation of renal vasoconstriction DefinitionCreatinine >1.5 mg/dL in a cirrhotic patientExclude other etiologiesOliguriaUnresponsive to 1.5-L fluid bolusProteinuria

Hepatorenal Syndrome (HRS)Type IProgressive renal failure on >2.5 mg/dL in 1.5 mg/dL over monthsGastroenterology. 2001;120:726.

Spontaneous Bacterial Peritonitis(SBP)Infection of the ascites without a source, such as intestinal perforationPrevalence between 10-30% in cirrhotic patientsMortality of 30%Diagnosis:PMN cells >250 /mm3 in ascitic fluidTreatment: 3rd generation cephalosporin for 5 daysGastroenterology. 2001;120:726.PMN=polymorphonuclear

Recommendations for the Treatment of HRS and SBPHepatorenal Syndrome (HRS)Albumin 1 g/kg + vasoactive drug (ie, octreotide, midodrine or terlipressin)Liver transplantationSpontaneous Bacterial Peritonitis (SBP)IV antibioticsAlbumin 1.5 g/kg within 6 hours of detectionAlbumin 1.0 g/kg at day 3 of antibiotic treatmentAmerican Association for the Study of Liver Disease. 2004.

Diagnostic paracentesisIndicationsNew-onset ascitesAdmission to hospitalClinical deteriorationFeverContraindicationsVirtually noneFibrinolysis or DIC

TechniqueAvoid abdominal scarsMidline if possibleMidline is avascularInferior to umbilicusRisk of entering bladder is lowLower quadrant approach

TechniqueSemirecumbent position is most commonDullness at site of needle entryUltrasound guidanceMetal needle1.5 inches22-gauge for diagnostic paracentesis16-gauge for therapeutic paracentesis

TechniqueDisinfect skin with iodine solutionLocal anesthetic for skin and subcutaneous tissueSterile glovesDrapes not necessaryZ-tractDo not aspirate continuously

ComplicationsProspective studyLow morbidityNo mortalityAbdominal wall hematomas are most common adverse eventSafe in coagulopathy

Fluid analysis

SAAGSerum-Ascites Albumin Gradient= serum albumin ascites albumin> 1.1 = portal hypertension < 1.1 = non-portal hypertension

SAAG

SAAG

Large volume (total) paracentesisCan be done as needed to relieve symptomsBenefits: comfort, nutrition, mobility, respiratory function, ?renal perfusionRisks: Post paracentesis circulatory dysfunction: prevented with 50 g albumin (transudates only)Hemorrhage, infection, perforation

Diagnostic paracentesis:AASLD Practice GuidelinesAbdominal paracentesis should be performed and ascitic fluid should be obtained from patients with clinically apparent new onset ascites

Initial lab investigation should include:Cell count and diffTotal protein, albumin -> calculate SAAG

Other studies can be ordered based on pretest probability of disease, including:Culture: routine, AFB, fungalChemistry: glucose, LDH, Amylase, TGCytology

BA Runyon, 2004. Hepatology 39:841

Low protein, high SAAGcirrhoticHigh protein, high SAAGcongestiveR sided CHFConstrictive pericarditisBudd-ChiariLow protein, low SAAGhypoalbuminemicNephroticEnteropathic High protein, low SAAGexudativeCancerTBHypothyroidPancreatic

Low protein: < 2.5 g/dl

High SAAG: > 1.1 g/dlParacentesis as a guide to diagnosis

Fluid AnalysisCell Count:PMNsHemorrhagic ascites- corrected PMNCultureUsually monomicrobial in SBPProtein and Albumin

Fluid AnalysisGlucoseUsually falls below in secondary bacterial peritonitisLDH- releases from PMN lysisIncreased in SBP; further elevated in secondary bacterial peritonitisAmylaseIncreased in pancreatitis and gut perforation

ConclusionsChronic liver disease (ie, hepatitis B) leads to development of cirrhosis, which in turn, may lead to complicationsIV albumin should be given in all patients undergoing large-volume paracentesisIV albumin + vasopressin analogs may be effective in the management of HRSIV albumin + antibiotics are the main therapy for spontaneous bacterial peritonitisParacenteses may be effective to reduce large ascites

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