Cirrhotic Ascites 01.pdf - Healthoracle.org

1. Culture fluid for Tuberculosis2. WBC Differential >50% Neutrophils (PMNs)1. Pancreatic Ascites (Fluid amylase >100U/L)1. Evaluate with abdominal CT2. Spontaneous Bacterial Peritonitis (singlecolony)1. Fluid total protein 50 mg/dl3. Fluid LDH 10,0002. Fluid total protein >1 g/dl3. Fluid glucose 225 U/L6. Ascites fluid color1. Transparent to cloudy yellow or clear (typical)2. Dark brown: Obtain quantitative fluid Bilirubin3. Milky: Obtain Triglyceride concentration4. Bloody: Adjust Leukocyte count1. Subtract 1 White Blood Cell per 750 RedBlood Cells2. Subtract 1 Neutrophil (PMN) per 250 RedBlood Cells7. Ascites fluid assorted labs1. Lactate Dehydrogenase2. Amylase3. pH4. Lipids5. Culture and cytology8. Diagnostics: Diagnostic Paracentesis1. Identify site at linea alba, 2 cm below Umbilicus2. Use 22 gauge needle with catheter9. Radiology1. Ultrasound abdomen or CT Abdomenwww.healthoracle.org 3

intravascular volume contraction. In most instances, hyponatremiaresponds to volume replacement with colloid, and fluid restrictionshould only be used in patients with serum sodium < 120 mmol/L.DiureticsDiuretics that block aldosterone receptors in the distal convolutedtubule are preferred because of the presence of hyperaldosteronismin patients with cirrhosis. Loop diuretics may be used in combination,but are ineffective when used alone. The initial starting dose ofspironolactone is 100 mg once daily and can be titrated up to amaximum of 400 mg once a day. Absorption of spironolactone isimproved if administered with food. The diuretic effect can be seenwithin 48 hours, but the peak onset of action is 2 weeks, due toimpaired metabolism in cirrhotic persons and a half-life of up to 5days. Therefore, the dose should be adjusted only once a week. Sideeffects include hyperkalemia and painful gynecomastia. Amiloride canbe used instead of spironolactone, starting at 5 mg per day. The latteris sometimes preferred because of its shorter half-life and quickeronset of action. However, it is much more expensive thanspironolactone and has also been shown to be less effective in arandomized, controlled trial.Both spironolactone and amiloride are weak diuretics and oftenrequire the addition of a loop diuretic such as furosemide.Furosemide effects are evident within 30 minutes of oraladministration, with a peak effect within 1-2 hours and duration ofaction of 4 hours. It is a potent diuretic but is not as effective asspironolactone alone. Furosemide prevents reabsorption of sodiumin the loop of Henley; without spironolactone, however, sodiumdelivered to the distal collecting duct is rapidly reabsorbed due tounopposed aldosterone action. Side effects of furosemide includehypokalemia, hypovolemia, hyponatremia, and increased renalammonia production. Hypokalemia is usually not a problem whenfurosemide is combined with a potassium-sparing diuretic.Intravenous administration of furosemide is not recommendedwww.healthoracle.org 6

ecause of good oral availability and because of the potential forcausing acute reductions in GFR. There is no advantage to usingother loop diuretics. The usual starting doses of diuretics are 100 mgof spironolactone and 40 mg furosemide. Doses can be titrated up toa maximum of 400 mg of spironolactone and 160 mg of furosemide.A ratio of 100:40 usually maintains normokalemia.Monitoring Response to Sodium Restriction and DiureticsCompliance with and response to sodium restriction and diureticscan be evaluated by taking the weight daily and checking the 24-hoururine collection for sodium. Completeness of urine collection isindicated by urinary creatinine levels of 15-20 mg/kg in males and10-15 mg/kg in females. Weight loss should be limited to 0.5 kg perday. More rapid weight loss can cause hypovolemia and renalinsufficiency, as fluid resorption from the peritoneal cavity is limitedto 700 mL per day. Patients with massive edema can tolerate morerapid fluid loss until the edema has resolved.In order for a patient with a serum sodium concentration of 140mmol/L on an 88-mmol/day diet to lose 0.5 kg/day or 0.5 L of fluid,the 24-hour urine collection should contain approximately 150 mmolof sodium (140 mmol/Lx 0.5 L + 78 mmol/day). If a 24-hour urinecollection is not possible, a random urine sodium-to-potassium ratioof > 1 predicts a > 78-mmol/day sodium excretion in 90% ofpatients. Noncompliance with a low-sodium diet is reflected by anadequate sodium excretion but with the patient not losing weight.Inadequate sodium excretion, on the other hand, necessitatesincreasing the doses of diuretics as tolerated up to the maximumrecommended level. Diuretics should be discontinued andconsideration should be given to the use of second-line therapy ifthere is evidence of encephalopathy, if serum sodium is < 120mmol/L despite fluid restriction, or if serum creatinine is > 2.0mg/dL (180 micromoles [mcmol]/day).Large-volume paracentesis, if performed for tense non-refractoryascites, should be followed by diuretics to prevent re-accumulation ofwww.healthoracle.org 7

fluid. In a study of 36 patients treated by total paracentesis plusintravenous albumin randomized to receive spironolactone 225mg/day vs placebo, only 18% of those receiving spironolactone hadrecurrence of ascites compared with 93% of those in the placebogroup (P < .0001). The use of 225 mg/day of spironolactone wasshown to be effective and safe in most cases, without increasedincidence of post-paracentesis circulatory dysfunction. Patientsshould also continue to observe sodium restriction.Cirrhosis is the late result of any disease that causesscarring of the liver. Patients with cirrhosis aresusceptible to a variety of complications that includeascites, hepatic encephalopathy, and portal hypertensivebleeding. Quality of life and survival are often improvedby the prevention and treatment of these complications.This chapter will review the general principles in thediagnosis and treatment of cirrhotic ascites. (Seeseparate Disease Management chapters for overviews ofhepatic encephalopathy and portal hypertensivebleeding).DEFINITIONAscites is defined as the accumulation of fluid in theperitoneal cavity. It is a common clinical finding with avariety of both extra-peritoneal and peritoneal etiologies(Table 1), but it is most often caused by liver cirrhosis.The development of ascites in a cirrhotic patientgenerally heralds deterioration in clinical status andportends a poor prognosis.PREVALENCEAscites is the most common major complication ofcirrhosis and is an important landmark in the naturalhistory of chronic liver disease. If observed for 10 years,approximately 60% of patients with cirrhosis willdevelop ascites requiring therapy and/or orthotopic livertransplantation. 2www.healthoracle.org 8

PATHOPHYSIOLOGYThe currently accepted theory of ascites formation is the"peripheral arterial vasodilation hypothesis" (Figure 1).This hypothesis does not directly refute olderhypotheses, but rather incorporates them into oneuniform theory that most matches actual hemodynamicdata.According to this theory, development of portalhypertension is the first abnormality to occur in cirrhoticpatients who develop ascites. Cirrhosis itself increasesthe resistance to blood flow within the liver, therebycausing the development of portal hypertension andshunting of blood to the systemic circulation. Portalpressures >12 mm Hg are generally required for theaccumulation of fluid in cirrhosis. This concept isimportant, since reducing portal pressure to

Mechanisms involved include the renin-angiotensinsystem, sympathetic nervous system, and antidiuretichormone (vasopressin). The ultimate effect is sodiumand water retention. In the late stages of cirrhosis, freewater accumulation is more pronounced than the sodiumretention and leads to a dilutional hyponatremia.Cirrhotic patients with ascites may therefore demonstrateurinary sodium retention, increased total body sodium,and dilutional hyponatremia, a challenging concept tomany physicians.SIGNS AND SYMPTOMSThe symptoms of ascites vary from patient to patient anddepend largely on the quantity of fluid. If trace ascites ispresent, the patient may be asymptomatic, and fluid isdetected only on physical or radiological examination. Ifa large amount of fluid is present, the patient maycomplain of abdominal fullness, early satiety, abdominalpain, or shortness of breath.Physical examination findings are equally variable. Theaccuracy of detecting ascites depends on the amount offluid present and the body habitués of the patient(detecting ascites may be more technically difficult inobese patients). If ascites is present, typical findingsinclude generalized abdominal distention, flank fullness,and shifting dullness. If the physical examination is notdefinitive, abdominal ultrasonography can be used toconfirm the presence or absence of ascites.www.healthoracle.org 10

established.Table 2:Grading Systems for AscitesSleisingerandFordtran 3InternationalAscitesClub 11Minimal 1+ Grade 1Moderate 2+ Grade 2Severe 3+ Grade 3Tense 4+ ''DIAGNOSISIf a non-cirrhotic patient develops ascites, diagnosticparacentesis with ascites fluid analysis is an essential partof the medical evaluation. In a patient with welltablishedcirrhosis, the exact role of a diagnostic paracentesis isless clear. Our opinion is that for a highly functionaloutpatient with documented cirrhosis, the newdevelopment of ascites does not routinely requireparacentesis. Cirrhotic patients should, however,undergo paracentesis in cases of (1) unexplained fever,abdominal pain, or encephalopathy, or (2) admission tothe hospital for any cause. It is common for hospitalizedcirrhotic patients to have infected ascites fluid(spontaneous bacterial peritonitis), even if no symptomsare present. This is particularly true in the event of asignificant gastrointestinal hemorrhage.www.healthoracle.org 11

the paracentesis needle is most commonly performed inthe left or right lower quadrants but can also beperformed safely in the midline. To minimize bleedingcomplications, care should be taken to avoid anyengorged and/or superficial blood vessels. The course ofthe inferior hypogastric artery (along the mid portion ofthe rectus abdominal muscle) should also be avoided.Abdominal ultrasound can guide the procedure if thefluid is difficult to localize or if initial attempts to obtainfluid are unsuccessful.Valuable clinical information can often be obtained bygross examination of the ascitic fluid (Table 3).Uncomplicated cirrhotic ascites is usually translucent andyellow. If the patient is deeply jaundiced, the fluid mayappear brown. Turbidity or cloudiness of the ascitic fluidsuggests that infection may be present, and furtherdiagnostic testing should be performed. Pink or bloodyfluid is most often caused by mild trauma, withsubcutaneous blood contaminating the sample. Bloodyascites is also associated with hepatocellular carcinoma orany malignancy-associated ascites. Milky fluid usually hasan elevated triglyceride concentration. Such fluid,commonly referred to as "chylous ascites," can be relatedto thoracic duct injury or obstruction or to lymphoma,but it is often related primarily to cirrhosis.Table 3:Gross Appearance of AscitesColor AssociationTranslucent or Normal/sterileyellowBrownHyperbilirubinemia(most common)www.healthoracle.org 12

Cloudy or tubidPink or bloodtingedGrossly bloodyMilky ("chylous")Gallbladder orbiliary perforationInfectionMild trauma at thesiteMalignancyAbdominal traumaCirrhosisThoracic duct injuryLymphomaMany ascitic fluid tests are currently available, yet theoptimal testing strategy has not been well established.Generally, if uncomplicated cirrhotic ascites is suspected,only an albumin concentration test and a cell count withdifferential are performed (Table 4). Less than 10 mL offluid placed in a "purple top" tube (containing ananticoagulant) is required to perform these basic tests.The albumin concentration test is used to confirm thepresence of portal hypertension by calculating the serumto-ascitesalbumin gradient, (SAAG), which isdetermined by subtracting the ascites albumin value froma serum albumin value obtained on the same day (ie.,Albumin serum - Albumin ascites = SAAG). The SAAG hasbeen proven in prospective studies to categorize ascitesbetter than any previous criteria. The presence of agradient >1.1 g/dL indicates with 97% accuracy that thepatient has portal hypertension-related ascites. Portalhypertension is usually caused by liver cirrhosis or, lesscommonly, outflow obstruction from right-sided heartfailure or Budd-Chiari syndrome. A SAAG of

hypertension-related ascites, and another cause should besought. The SAAG does not need to be repeated afterthe initial measurement.Table 4:RoutineCell countwithdifferentialAlbuminAscitesculture*Ascites Fluid TestingSometimesUsefulTotal proteinRarelyHelpfulpHLactosedehydrogenase LactateGlucoseGram stainAmylaseTriglyceridesBilirubinCytologyTB smear andculture*Suspected infection and/or correctedPMN countis >250The cell count and differential are used to determinewhether the patient is likely to have spontaneousbacterial peritonitis. Patients with an asciticpolymorphonuclear (PMN, or absolute neutrophil) countgreater >250 cells/mm 3 should receive empiricantibiotics, and additional fluid should be inoculated intoblood culture bottles to be sent for culture. The PMNcount is calculated by multiplying the white cells/mm 3 bywww.healthoracle.org 14

of ascites fluid may decrease infection-related morbidity.Furthermore, treating ascites can dramatically improvequality of life by decreasing abdominal discomfortand/or dyspnea. General ascites management in allpatients should include minimizing consumption ofalcohol, nonsteroidal anti-inflammatory drugs (NSAIDs),and dietary sodium. The use of more aggressiveinterventions depends on the severity of ascites and nonresponseto these general measures. This includes use oforal diuretics, therapeutic (or large-volume) paracentesis,trans-jugular intra-hepatic portosystemic shunt (TIPS),and orthotopic liver transplantation (Figure 2).General ManagementAll patients with cirrhotic ascites should be encouragedto minimize consumption of alcohol. Even if alcohol isnot the cause of their liver disease, cessation may lead todecreased fluid and improved response to medicaltherapies. Patients with ascites should also minimize useof all NSAIDs. NSAIDs inhibit the synthesis of renalprostaglandin and can lead to renal vasoconstriction,decreased diuretic response, and acute renal failure.Lastly, ascites patients should be counseled to limit theirsodium consumption to no more than 2 g/day. Avoidingfrozen or canned foods in combination with "throwingaway the salt shaker" (using other spices or saltsubstitutesto season freshly prepared foods) can usuallyaccomplish this restriction. Since fluid passively followssodium, a salt restriction without a fluid restriction isgenerally all that is required to decrease the amount ofascites. In patients with minimal fluid, the restriction ofalcohol, NSAIDs, and salt may be all that is needed toadequately control ascites formation.Moderate-Volume AscitesPatients with moderate fluid overload who do notwww.healthoracle.org 16

espond to the above measures should be considered forthe addition of pharmacologic therapy. A rapid reductionof ascites is often accomplished simply with initiation oflow-dose oral diuretics. In general, patients withmoderate ascites do not need to be admitted to thehospital unless there are other, accompanyingcomplications. First-line diuretic therapy for cirrhoticascites is dual use of oral spironolactone (Aldactone) andfurosemide (Lasix). Beginning daily doses are 100 mg ofspironolactone and 40 mg of furosemide orally. If weightloss and natriuresis are inadequate, both drugs can besimultaneously increased after 3 to 5 days to 200 mg ofspironolactone and 80 mg of furosemide. To maintainnormal electrolyte balance, the use of the 100:40-mgratio of spironolactone to furosemide is generallyrecommended. Maximum accepted doses are 400 mgand 160 mg daily of spironolactone and furosemide,respectively.The response to diuretics should be carefully monitoredon the basis of changes in body weight, laboratory tests,and clinical assessment. Patients taking diuretics shouldbe weighed daily, and the rate of weight loss should notexceed >0.5 kg/day in the absence of edema and >1kg/day when edema is present. Serum potassium, bloodurea nitrogen (BUN) and creatinine should be seriallyfollowed. In the event of marked hyponatremia, hyperorhypokalemia, renal insufficiency, dehydration, orencephalopathy, diuretics should be reduced ordiscontinued. Routine measurement of urinary sodium isnot necessary but can be helpful in identifying noncompliancewith dietary sodium restriction. Patientsexcreting >78 mmol/day of sodium (88 mmol dietaryintake—10 mmol non-urinary excretion) detected on a24-hour urinary collection should be losing weight. Ifnot, they are noncompliant with their diet and should bewww.healthoracle.org 17

eferred to a dietician. The spot urine sodium-topotassiumratio may ultimately replace the cumbersome24-hour collection: a random urine sodium concentrationthat is greater than the potassium concentration has beenshown to correlate with a 24-hour sodium excretion >78 mmol per day with approximately 90% accuracy.Because of the potential severe complications associatedwith diuretic use, patients with ascites should be assessedby a health care provider at least once weekly until theyare clinically stable.Large-Volume AscitesLarge-volume ascites is defined as intra-peritoneal fluidin an amount that significantly limits the activities ofdaily life. With additional fluid retention, the abdomencan become progressively distended and painful. This iscommonly referred to as "massive" or "tense" ascites.Large-volume ascites can usually be managed in theoutpatient setting as long as no additional complicationsare present.Therapeutic (or large-volume) paracentesis is a wellestablishedtherapy for large-volume ascites. However,the use of post-procedural colloid, usually albumin,continues to be a controversial issue. Studies have shownthat patients who do not receive intravenous albuminafter large-volume paracentesis develop significantlymore changes in their serum electrolytes, creatinine, andrenin levels. The clinical relevance of these findings,however, is not well established. In fact, no study to datehas been able to demonstrate decreased morbidity ormortality in patients given no plasma expanderscompared with patients given albumin after paracentesis.In view of the high cost of albumin and its uncertainclinical role, more studies certainly need to be conducted.In the meanwhile, current practice guidelines of thewww.healthoracle.org 18

American Association for the Study of Liver Diseases(AASLD) state that it is reasonable, although notmandatory, to give albumin for paracentesis greater that5 L. Although no direct comparisons have ever beenstudied, 25% albumin at doses of 5 to 10 grams per literof ascites removed is generally used.In order to prevent re-accumulation of ascites fluid,patients with large-volume ascites should be counseledon limiting consumption of alcohol, NSAIDs, andsodium. They should also be placed on an aggressivediuretic regimen. Diuretic-sensitive patients are generallytreated with lifestyle modifications and medications, notserial paracentesis.Refractory AscitesRefractory ascites occurs in 5% to 10% of cirrhoticascites patients and portends a poor prognosis. Thedefinition of refractory ascites is (1) lack of response tohigh-dose diuretics (400 mg of spironolactone and 160mg of furosemide per day) while remaining compliantwith a low-sodium diet, or (2) frequent ascites recurrenceshortly after therapeutic paracentesis. Patients withrecurrent side effects from diuretic therapy, includingsymptomatic hyponatremia, hyper- or hypokalemia, renalinsufficiency, or hepatic encephalopathy, are alsoconsidered to have refractory ascites. Treatment optionsinclude frequent large-volume paracentesis with orwithout albumin infusion, placement of a trans-jugularintra-hepatic portosystemic shunt (TIPS) or livertransplantation. Surgical peritoneovenous shunts (ie,LeVeen or Denver) have essentially been abandonedsince controlled trials showed poor long-term patency,an excessive number of complications, and no survivaladvantage over medical therapy.www.healthoracle.org 19

Frequent therapeutic paracentesis with or withoutalbumin infusion is the most widely accepted treatmentfor patients with refractory ascites (see Large-VolumeAscites section above for controversy and dosingregarding albumin use). For those who have loculatedfluid or are unwilling or unable to receive frequentparacentesis, TIPS placement can also be considered. Inthe appropriately selected patient, TIPS is highlyeffective for preventing ascites recurrence by decreasingthe activity of sodium-retaining mechanisms andimproving renal function. Ongoing studies willdetermine if TIPS may also provide a survival benefit.In the United States, TIPS is most commonly performedunder conscious sedation by an interventionalradiologist. The portal system is accessed through thejugular vein, and the operator inserts a self-expandingshunt between the portal (high-pressure) and hepatic(low-pressure) veins. The ultimate goal of the procedureis to lower portal pressures to

portends a particularly poor prognosis, immediatereferral to an experienced liver transplantation center isrecommended.OUTCOMESTwo-year survival for a patient with cirrhotic ascites isapproximately 50%. Once patients become refractory toroutine medical therapy, 50% die within 6 months and75% within 1 year. Because liver transplantation isassociated with 2-year survival rates of almost 85%, itshould be considered an important treatment option inall appropriate patients.ClassificationAscites exists in three grades:• Grade 1: mild, only visible on ultrasound• Grade 2: detectable with flank bulging and shifting dullness• Grade 3: directly visible, confirmed with fluid thrillCausesCauses of high SAAG ("transudate") are:• Cirrhosis - 81% (alcoholic in 65%, viral in 10%, cryptogenic in6%)• Heart failure - 3%• Budd-Chiari syndrome or veno-occlusive disease• Constrictive pericarditisCauses of low SAAG ("exudate") are:www.healthoracle.org 21

• Cancer (primary peritoneal carcinomatosis and metastasis) -10%• Tuberculosis - 2%• Pancreatitis - 1%• Serositis• Nephrotic syndromePathophysiologyAscitic fluid can accumulate as a transudate or an exudate. Amountsof up to 25 liters are fully possible.Roughly, transudates are a result of increased pressure in the portalvein (>8 mmHg, usually around 20 mmHg), e.g. due to cirrhosis,while exudates are actively secreted fluid due to inflammation ormalignancy. As a result, exudates are high in protein, high in lactatedehydrogenase, have a low pH (

Spontaneous chylous ascites of cirrhosisThe spontaneous development of chylous ascites in patients withcirrhosis is documented, but its clinical features are not well defined.The incidence of this complication of chronic liver disease was 0.5%in ascitic patients in our liver unit. These patients were older than acontrol group with non-chylous cirrhotic ascites and, despite betterliver tests, appeared to have a higher diuretic requirement. Severalhad disabling, recurrent spontaneous encephalopathy. Themechanism of chylous ascites in cirrhosis is probably portalhypertension causing lymphatic rupture; however, the fact thatserum-to-ascites albumin gradients were similar in the two groups,indicating similar degrees of portal hypertension, suggests that otherfactors also play a role. Spontaneous transformation of previouslyclear ascites appeared to be associated with a poor prognosis. Incontrast, the appearance of chylous ascites de novo in a cirrhoticpatient appeared to have a more favorable outcome. Conservativemanagement is recommended for most patients, as the degree oftheir liver disease appears to be the most important factordetermining prognosis.Respiratory mechanics in patients with tense cirrhotic ascitesLung volumes are decreased by tense ascites and increase after largevolume paracentesis (LVP). The overall effect of ascites and LVP onthe respiratory function is poorly understood. We studied eightcirrhotic patients with tense ascites before and after LVP. Inspiratorymuscle force (maximal trans-diaphragmatic pressure (Pdi, max), andthe lowest pleural pressure (Pp1, min)) was assessed while thepatients were seated. Rib cage and abdominal volume displacements,as well as pleural and gastric pressures were measured during quietbreathing while the patients were supine. Pdi, max and Ppl, min werenormal and did not change after LVP (from 84.2+/-19.7 to 85.2+/-17.0 cmH2O and from 68.3+/-19.7 to 74+/-15.9 cmH2O,respectively). The abdominal contribution to the generation of tidalvolume was greater than that of the rib cage (79 vs 21%), a patternwww.healthoracle.org 23

which did not change after LVP (73 and 27%). Before LVP, tidalswings both of pleural pressure (Ppl, sw) and trans-diaphragmaticpressure (Pdi, sw) were large (15.3+/-4.3 and 18.5+/-3.9 cmH2O,respectively) and the load on inspiratory muscles was increased as aconsequence of elevated dynamic elastance of the lung (El, dyn)(11.4+/-2.6 cmH2O x L(-1)) and ("intrinsic") positive end-expiratorypressure (PEEPi) (4.3+/-3.5 cmH2O). LVP reduced the load on theinspiratory muscles, as shown by the significant decrease in Ppl, sw(10.6+/-2.0 cmH2O), Pdi, sw (12.8+/-3.0 cmH2O), El, dyn (10.0+/-2.0 cmH2O x L(-1)) and PEEPi (1.1+/-1.3 cmH2O). The amount offluid removed was closely related to changes in Ppl, sw and PEEPi.We conclude that the strength of the inspiratory muscles is normal orreduced in seated cirrhotic patients. In the supine position, tenseascites results in an increase in lung elastic load and development ofpositive end-expiratory pressure, with a consequent overload andincreased activation of inspiratory muscles. Large volumeparacentesis decreases overloading and activation, but does notchange the strength of the inspiratory muscles.www.healthoracle.org 24