malignantascites.pptx medicine health111

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1. Ascites

2. Ascites is the pathologic accumulation of fluid within the peritoneal cavity. It is the most common complication of cirrhosis and occurs in about 50% of patient with decompensated cirrhosis in 10 years. The development of ascites denotes the transition from compensated to decompensated cirrhosis.

3. ASCITIC FLUID ? What is in the ascetic fluid : 1. Proteins ( Albumin) 2.WBC 3.Lipids 4. Bile acids The main issues that arise regarding ascites are: Is the fluid infected? Is portal hypertension present?

4. Initial tests that should be performed on the ascitic fluid include : 1. Appearance assessment ( eg , clear, bloody, cloudy, milky) 2. Serum-to-ascites albumin gradient determination (SAAG) 3.Cell count and differential 4.Total protein concentration

5. Appearance   The gross appearance of the ascitic fluid can be helpful in the differential diagnosis 1. Clear   Uncomplicated ascites in the setting of cirrhosis is usually translucent yellow; it can be completely clear if the bilirubin is normal and the protein concentration is very low. 2. Turbid or   cloudy   Spontaneously infected fluid is frequently turbid or cloudy. 3. Opalescent   Infrequently, ascitic fluid in the setting of cirrhosis is "opalescent" and has a slightly elevated TG concentration, misinterpreted as "pus. 4. Milky   Milky fluid usually has a triglyceride concentration that exceeds the serum concentration, is greater than 200 mg/ dL  (2.26  mmol /L), and is often greater than 1000 mg/ dL  (11.3  mmol /L); such specimens are referred to as " chylous ascites“ 5. Pink or   bloody (and corrected neutrophil count)   Pink fluid usually has a red cell concentration of >10,000 per mm 3 . Most bloody samples are due to a "traumatic tap" 6. Brown  – Deeply jaundiced patients have brown ascitic fluid with a bilirubin concentration approximately 40 percent of the serum value.

6. SERUM-TO-ASCITES ALBUMIN GRADIENT  —   accurately identifies the presence of portal hypertension  ≥ 1.1 g/ dL  (≥11 g/L) predicts that the patient has portal hypertension with 97 percent accuracy . <1.1 g/ dL  (<11 g/L) indicates that the patient does not have portal hypertension

7. The total protein concentration may also help differentiate uncomplicated ascites from cirrhosis from cardiac ascites, both of which have a SAAG ≥1.1 g/ dL  (≥11 g/L). In the case of ascites from cirrhosis, the total protein is <2.5 g/ dL  (<25 g/L), whereas in cardiac ascites it is ≥2.5 g/ dL (≥25 g/L ). In patients with nephrotic ascites, the SAAG is <1.1 g/ dL  (<11 g/L), and the total protein in the ascites of <2.5 g/ dL  (<25 g/L).

8. Cell count with differential  —  the single most useful test performed to evaluate for infection and should be ordered on every specimen   The cell count should be available within one hour, while the culture takes several hours to days Antibiotic treatment should be considered in any patient with a corrected neutrophil count ≥250/mm 3  

9. The white blood cell and neutrophil counts need to be corrected in patients with bloody samples. One white blood cell should be subtracted from the white blood cell count for every 750 red blood cells to yield the "corrected white blood cell count," and one neutrophil should be subtracted from the absolute neutrophil count for every 250 red blood cells to yield the "corrected neutrophil count" In bloody ascites, the corrected neutrophil count is frequently <0 due to remote hemorrhage with lysis of neutrophils.

10. Measurement of total protein, glucose, and lactate dehydrogenase (LDH) in ascites may also be of value in distinguishing SBP from bowel perforation into ascites Patients with ascitic fluid that has a corrected neutrophil count ≥250 cells/mm 3  and meets two out of the following three criteria are unlikely to have SBP and warrant immediate evaluation to determine if bowel perforation into ascites has occurred : Total protein >1 g/ dL Glucose <50 mg/ dL  (2.8  mmol /L) LDH greater than the upper limit of normal for serum

11. T ests that may be performed to aid in confirming a diagnosis include: Culture with bedside inoculation of aerobic and anaerobic blood culture bottles (infection, bowel perforation) Glucose concentration (malignancy, infection, bowel perforation) Lactate dehydrogenase concentration (malignancy, infection, bowel perforation) Gram stain (suspected bowel perforation) Amylase concentration (pancreatic ascites or bowel perforation) Tuberculosis smear, culture, and adenosine deaminase activity ( tuberculous peritonitis) Cytology and possibly carcinoembryonic antigen level (malignancy) Triglyceride concentration ( chylous ascites) Bilirubin concentration (bowel or biliary perforation) Serum pro-brain natriuretic peptide (heart failure)

12. Total protein concentration  —  Ascitic fluid can be classified as an exudate if the total protein concentration is ≥2.5 or 3 g/ dL  and a transudate if it is below this cutoff . However , the exudate/transudate system of ascitic fluid classification has been replaced by the SAAG, which is a more useful measure for determining whether portal hypertension is present

13. Culture   — Cultures of ascitic fluid should be obtained on specimens from patients who are being admitted to the hospital with ascites and those who deteriorate with fever, abdominal pain, azotemia , acidosis, or confusion. By comparison, therapeutic paracentesis samples in patients without symptoms of infection do not need to be cultured. An adequate volume of ascitic fluid (generally 10 mL per bottle, but the amount varies according to the manufacturer of the bottle) should be inoculated into aerobic and anaerobic blood culture bottles at the bedside .

14. Cytology  – Almost 100 percent of patients with peritoneal carcinomatosis will have positive ascitic fluid cytology due to the presence of viable malignant cells exfoliating into the ascitic fluid . However , only about two-thirds of patients with malignancy-related ascites have peritoneal carcinomatosis . As a result, the overall sensitivity of cytology smears for the detection of malignant ascites is 58 to 75 percent.

15. Carcinoembryonic antigen   concentration  – Measurement of carcinoembryonic antigen (CEA) in ascitic fluid has been proposed as a helpful test in detecting malignancy-related ascites. However , the study that validated CEA was small and did not subgroup patients based on the type of cancer. CEA may be of some utility in ascitic fluid analysis, but its precise value remains unclear.

16. Triglyceride   concentration  – A triglyceride concentration should be obtained on ascitic fluid that is milky. Chylous ascites has a triglyceride content greater than 200 mg/ dL  (2.26  mmol /L) and usually greater than 1000 mg/ dL  (11.3  mmol /L)  Bilirubin   concentration  – The bilirubin concentrate on should be measured in patients with brown ascites. As mentioned above, an ascitic fluid bilirubin value greater than the serum suggests bowel or biliary perforation into ascites Serum pro-brain natriuretic peptide   concentration  – Measurement of pro-brain natriuretic peptide in serum can help distinguish ascitic fluid due to cirrhosis from ascitic fluid due to heart failure

17. Appropriate treatment of patients with ascites depends on the cause of fluid retention . Patients with low SAAG (<1.1g/dl) ascites usually do not have portal hypertension and, with the exception of nephrotic syndrome, do not respond to salt restriction and diuretics. patients with a high SAAG (≥1.1 g/ dL ) have portal hypertension and usually are responsive salt restriction and diuretics.

18. Malignant ascites Abnormal intra-peritoneal collection of fluid as a result of malignancy Indicates late disease state of malignant disease and indicates poor prognosis Common with cancers such as: ovarian, pancreatic, colonic, breast, gastric and endometrial Management is usually palliative aimed to improve quality of life

19. E pidemiology Accounts for about 10% of all ascites, and 15-50% of patients with malignancy would develop ascites About 20% may have unknown primary Patients usually have < than 6 months to live except in some cases of breast and ovarian malignancies Ovarian cancer had the highest proportion of patients who developed ascites at 37.7%, followed by pancreaticobiliary cancers (21%), gastric cancer (18.3%), esophageal cancer (4.0%), colorectal cancer (3.7%), and breast cancer (3.0%).

20. carcinomatosis/malignant ascites

21. Pathophysiology of malignant ascites generation Imbalance between normal peritoneal fluid production and absorption Lymphatic obstruction by tumor cells excess vascular permeability Tumor-specific effects such as excess metalloproteinase production. Over-secretion/production By tumor Leaky capillaries (VEGF, VPF, 45-Kd Glycoproteins) in ovarian, gastric, colonic, pancreatic, hepatic and omental mets Under-absorption Malignant lymphatic blockages Budd-chiari syndrome Combination of factors

22. Symptoms : Gastrointestinal symptoms include : Indistension Nausea Vomiting Patients experience dyspnea , as well as weight gain and edema. Women with ovarian cancer describe Bloating Swelling Fatigue urinary frequency Constipation abdominal and pelvic pain, back pain, Anorexia and vaginal bleeding +/- gastrointestinal symptoms such as indigestion, constipation, abdominal cramping, diarrhea, gas, or movement in pelvis Ascites can cause significant symptoms referable to the gastrointestinal and genitourinary tract.

23. Management: D iagnosis History To suggest malignancy Intestinal or gynaecological Extraintestinal Metastasis Complications e.g coagulopathy To rule out differentials Previous treatment Physical exam In keeping with malignancy Cachexia, Palor, jaundice, Virchow’s node, edema Sister Mary-Josephs nodule, Blummer’s shelf, adnexiae Abd distension, ecchymosis

24. Management: Diagnosis Clinical Clinical exam: puddle sign, shifting dullness fluid thrill Ascitic fluid tap Straw, chylous, haemorrhagic Diagnostic Laparoscopy Image guided biopsies Radiological USS ≥ 100mls CT MRI Others: Skeletal survey PET scans

25. Mana g eme n t Presentation Elective Emergency SBP Respiratory distress Complicated Hernias Resuscitation Fluids Oxygen Pain control Antibiotics Correction of anaemia Correction of dyselectrolytaemia

26. Diagnosis: Laboratory Test Importance Diagnostic accuracy Cytology (Gold standard) Malignant cells Usually around 50-60% (up to 89.5% when combined with human gonadotropin B) Telomerase activity Sensitivity of around 76% and specificity of about 95.7% Ascitic Sialic acid Differentiate malignant from non-malignant fluid Diagnostic accuracy of about 82%. Cut off 300mg/l Ascitic fibronectin Increased deection Diagnostic accuracy of 85% with No false positive. Cut off ?7.5mg/dl Tumor markers Guide to possible primary tumor origin Ascitic immunohistochemistry Tumor origin Image guided Biopsies Tumor origin It provides a site-specific primary tumor diagnosis in 93% of cases

27. Diagnosis: Laboratory Non-specific SAAG <1.1 = exudation (97% accuracy) Total protein level ≥ 2.5g/dl SBP = 250/mm3, m/c/s Ascitic fluid amylase = ↑in perforation and IO ? usefulness Ascitic lactate Ascitic pH Ascitic cholesterol Up to 25% of patient with Cirrhosis Have protein rich ascites while up to 18% of Patients with malignant ascites may have low Ascitic protein level

28. Management options: No generally accepted evidence-based guideline AIM: to reduce tension, improve comfort and quality of life MEDICAL, MINIMALLY INVASIVE & SURGICAL Reduce immediate discomfort (‘external’ ascitic drainage) Reduce ascites production (intra-cavitary or systemic) Improve ascites reabsorption (shunting procedures) Combination of above

29. Medical Management: role of diuretics Agent Dose Study Spironolactone 150-450mg/day P.O Greenway et al 1982 Frusemide 100-200mg I.V Razis 1976 Bumetanide 3-5mg/day Razis 1976 Methylclothiazide + Spironolactone 5mg/day + 50-100mg/day Gough et al 1993 Spironolacone + Frusemide 100-200mg/day + frusemide 40- 80mg/day Sharma 1995 When life expectancy is > 4 weeks Commonly used by physicians as the first line of care but efficiency reported has been poor (<45%) There are no randomized controlled trials assessing the efficacy of diuretic therapy in malignant ascites. Poorer response in those with protein-rich peritoneal fluids than serous fluids of direct hepatic mets

30. Medical Management: Use of octreotide Reduce intestinal secretion and increase rate of absorption May be useful in chylous ascites Dose 200-600mcg by subcute catheter over 24hr period

31. Minimally invasive techniques Abdominocentesis (large external drainage procedures) Intra-cavitary treatments: cytotoxics, immunotoxics/biologics, radioactive agents HIPEC

32. (A) “External” Large volume drainage procedures: Abdominal Paracentesis Done within 48hrs of presentation, Preferably removed within 24hr of insertion Endoscopic USS guided Paracentesis (EUS-P) Issues with rate of flow Issues with volume per ‘tap’ ? use of albumin except for severe hypovolaemia Empty bladder Ensure analgesia Contraindicated in: DIC Severe bowel distension Multiple abdominal surgeries Multiple small loculations

33. Abdominal paracentesis 8G x 16cm long catheter with 3-way lock

34. Surgical Management Diagnostics of underlying dx Treatment of ascites (shunting procedures) Cytoreductive surgeries Open or laparoscopic

35. Shunting procedures Peritoneo-venous shunts More popular, 70% success rate Denver & Le Veen Contraindicated in hemorrhagic, loculated, infected and chylous ascites, ascitic protein > 4.5g/L. Don’t use in CCF and RF. ? Benefit in Px with <1-3month life expectancy Peritoneo-vesical shunts Less popular Contraindicated in haematuria, UTI Breast and ovarian cancer patients seem to respond better (≥ 50%) than patients with malignant ascites from GI origin (10-15%)

36. Denver Shunts Denver Biomedicals Originally a V-P shunt, currently marketed by the CareFusion Corporation Kirsch et al modification of Denver V-P shunt, 1970 Allows retrograde flow when the peritoneal pressure is 1cm of H2O above intrathoracic pressure Manual pumping best in supine position

37. The most common cause of portal hypertension related ascites is cirrhosis which usually caused by Chronic hepatitis C Alcohol abuse Obesity/nonalcoholic steatohepatitis (NASH) Most important step in treating this form of ascites is to treat the underlying cause of liver disease.

38. Natural history of cirrhotic ascites

39. First-Line Cessation of alcohol use (when present) Sodium restricted diet and diet education Dual diuretics usually spironolactone and furosemide orally with single daily dosing Discontinue non-steroidal anti-inflammatory drugs Evaluation for liver transplantation

40. Second-Line Discontinue beta blockers, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers Consider adding midodrine especially in the profoundly hypotensive patient Serial therapeutic paracenteses Evaluation for liver transplantation Transjugular intrahepatic portasystemic stent-shunt (TIPS)

41. Third-Line Peritoneovenous shunt

42. FIRST-LINE TREATMENT Most important step in treating ascites in cirrhosis due to ethanol is by ceasing alcohol consumption. One study demonstrates that patients who have Child-Pugh C cirrhosis due to alcohol and who stop drinking have an approximately 75% 3-year survival , but all those who continue to drink die in 3 years. Baclofen has been shown in a randomized trial to reduce alcohol craving and reduce alcohol consumption.

43. Liver diseases other than alcohol-related, hepatitis B and autoimmune hepatitis are less reversible. By the time ascites is present, these patients may be best served by referral for liver transplantation evaluation rather than protracted medical therapy

44. DIET Education regarding dietary sodium restriction (2000 mg per day [88 mmol per day]) Fluid loss and weight change are directly related to sodium balance in patients with portal hypertension-related ascites patient should be educated in a saltrestricted diet by a dietician

45. URINE SODIUM MONITORING A random “spot” urine sodium concentration that is greater than the potassium concentration correlates well with a 24-hour sodium excretion. This urine sodium/ potassium ratio may replace the cumbersome 24-hour collection. When this ratio is >1, the patient should be losing fluid weight. The higher the ratio, the greater the urine sodium excretion.

46. DIURETICS Usual diuretic regimen consists of single morning doses of oral spironolactone (100 mg) and furosemide (40 mg). Starting with both drugs appears to be the preferred approach in achieving rapid natriuresis and maintaining normokalemia .

47. Doses of both oral diuretics can be increased simultaneously every 3 to 5 days (maintaining the 100 mg:40 mg ratio) if weight loss and natriuresis are inadequate. This ratio maintains normokalemia . Usual maximum doses are 400 mg per day of spironolactone and 160 mg per day of furosemide .

48. All diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration <120mmol/L) progressive renal failure, worsening hepatic encephalopathy, or incapacitating muscle cramps

49. Hyponatremia Serum sodium <130 mEq /L Present in 22% of patients with ascites Risk factor for encephalopathy and the HRS syndrome Water restriction (1–1.5 L/day) No effective therapies, vaptans have a transient effect Poor prognostic marker

50. REFRACTORY ASCITES Defined as ascites that cannot be mobilized or prevented from recurring by medical therapy. Diuretic resistant - ascites is not mobilized despite maximal diuretic dosage Diuretic intractable - ascites development of diuretic‐induced complications that preclude the use of an effective diuretic dosage.

51. Dietary history use of non-steroidal anti-inflammatory drugs, angiotensin -converting enzyme inhibitors, angiotensin receptor blockers patient compliance with the treatment regimen

52. Treatment of refractory ascites First line: Serial therapeutic paracenteses Relapse is the rule Second line: TIPS When paracenteses >1–2/month MELD <15 Third line: Peritoneovenous shunt Non‐LVP, non‐TIPS candidates

53. Criteria for TIPS Age <65 years Child–Pugh score ≤12 points MELD score <18 No alcoholic hepatitis Cardiac ejection fraction ≥60% No severe spontaneous hepatic encephalopathy

54. Beta blockers may shorten survival in refractory ascites . Oral midodrine 7.5 mg three times daily has been shown in a randomized trial to increase urine volume, urine sodium, mean arterial pressure, and survival.

55. SBP

56. CLASSIFICATION 1. Spontaneous ascitic fluid infection - SBP 2. Secondary bacterial peritonitis Gut perforation Non perforation 3. Monomicrobial or polymicrobial nonneutrocytic bacterascites

57. Definitions PMN cells/mm3 Culture Surgical source of infection SBP ≥250 +/- No MNNB <250 Monomicrobial No PNNB <250 Polymicrobial No Secondary bacterial peritonitis ≥250 + present

58. Prognosis With SBP, 10–33% of patients will die during that hospital admission. The 1‐year probability of SBP recurrence is 69% and median survival of a patient who develops SBP is 9 months. Main predictors of mortality Development of renal dysfunction Lack of response to initial empirical antibiotic therapy Nosocomial infection

59. Treatment Third generation cephalosporins usually cefotaxime administered intravenously at a dose of 2 g every 12 h for 5–7 days. Amoxycillin‐clavulanic acid is as effective as cefotaxime . Repeat paracentesis after 48 h of start of treatment Lack of response (decrease in PMN <25% from baseline)

60. Multidrug‐resistant bacteria are health‐care associated or nosocomial Extended spectrum antibiotics (e.g. carbapenems , imipenem / cilastatin , piperacillin / tazobactam ) should be used as initial empirical therapy Intravenous albumin- A dose of 1.5 g/kg body weight should be given within 6–12 hours of diagnosis of SBP with a 1 g/kg dose at 72 hours.

61. PREVENTION A prospective study reported in 1988 documented a 69% recurrence rate at 1 year. An ascitic fluid protein concentration of <1.0 g/ dL was the best predictor of recurrence. Antibiotic prophylaxis: Prior SBP Gut hemorrhage Primary prevention of SBP

62. Take home message Mainstay of therapy of patients with cirrhosis and ascites is dietary sodium restriction and diuretics. Standard medical therapy is effective in >90% of patients. Therapeutic paracentesis should be performed to acutely treat tense ascites and as second-line chronic treatment of a portion of the 10% of patients who are refractory to medical therapy. Many patients who are refractory to medical therapy should be considered for TIPS. Patients who are liver transplant candidates and who develop refractory ascites should be prioritized for transplantation.

63. Take home message Diagnosis requires a high degree of suspicion Clinical features may be absent and peripheral WBC normal Ascitic protein usually <1 g/ dL Usually monomicrobial and Gram‐negative Start antibiotics if ascites >250 mm polymorphs Concomitant albumin use, particularly if renal dysfunction or jaundice Antibiotic prophylaxis 20% die 69% recur in 1 year

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