A DISSERTATION ON
THE DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS USING LEUKOCYTE ESTERASE STRIP IN
COMPARISON WITH NUETROPHIL LYMPHOCYTIC RATIO OF THE ASCITIC FLUID IN CIRRHOTIC
PATIENTS
Dissertation Submitted to THE TAMILNADU
Dr.M.G.R. MEDICALUNIVERSITY CHENNAI - 600 032
in partial fulfillment of the regulations for the award of the degree of M.D. GENERAL MEDICINE BRANCH-I
COIMBATORE MEDICAL COLLEGE COIMBATORE – 641018.
MAY 2019
CERTIFICATE BY THE GUIDE
This is to certify that this dissertation in “THE DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS USING LEUKOCYTE ESTERASE STRIP IN COMPARISON WITH NUETROPHIL LYMPHOCYTIC RATIO OF THE ASCITIC FLUID IN CIRRHOTIC PATIENTS” is a bonafide research work done by Dr.NAVEEN BABU.K, under my guidance during the academic year 2016-2019. This has been submitted in partial fulfillment of the award of M.D. Degree in General Medicine (Branch-I) by The Tamil Nadu Dr.M.G.R Medical University, Chennai-600 032.
Date: Professor and Guide
Department of General Medicine Coimbatore Medical College
Dr. Kumar Natarajan M.D., Date: Professor & Head of Department
Department of General Medicine Coimbatore Medical College
Date: Dr. B. Asokan M.S., M.Ch (Plastic) Dean
Coimbatore Medical College Coimbatore
DECLARATION
I Solemnly declare that the dissertation titled “THE DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS USING LEUKOCYTE ESTERASE STRIP IN COMPARISON WITH THE NUETROPHIL- LYMPHOCYTIC RATIO OF THE ASCITIC FLUID IN CIRRHOTIC PATIENTS” was done by me from February 2017 to February 2018 under the guidance and supervision of Prof.Dr.S.USHAM.D., This dissertation is submitted to The Tamilnadu Dr.M.G.R. Medical University towards the partial fulfilment of the requirement for the award of MD degree in General Medicine (Branch 1)
Place: Coimbatore DR.K.NAVEEN BABU Date:
ACKNOWLEDGEMENT
I wish to express my sincere thanks to our respected Dean Dr.B.ASOKAN M.S.,MCh, for having allowed me to conduct this study in our hospital.
I express my heartfelt thanks and deep gratitude to the Head of the Department of Medicine Prof. Dr KUMAR NATARAJAN M.D., for his generous help and guidance in the course of the study
I sincerely thank PROF. DR.S.USHA M.D., for the valuable help and cooperation and allowing me to use institutional facilities.
I am extremely grateful to HOD, DR LALITHA Department of Pathology, for their valuable help and cooperation and allowing me to use institutional facilities.
I sincerely thank my Asst. Professors DR.P.BALAMURUGAN M.D., and DR.A.ALAGUTHIYAGARAJAN M.D., for their guidance and help.
I thank all my PATIENTS, who formed the backbone of this study without whom this study would not have been possible.
Lastly, I am ever grateful to the ALMIGHTY GOD for always showering His blessings on me and my family
DR.K.NAVEENBABU
CERTIFICATE – II
This is to certify that this dissertation work titled “THE DIAGNOSIS OF SPONTANEOUS BACTERIAL PERITONITIS USING LEUKOCYTE ESTERASE STRIP IN COMPARISON WITH THE NUETROPHIL - LYMPHOCYTIC RATIO OF THE ASCITIC FLUID IN CIRRHOTIC PATIENTS” of the candidate DR.K.NAVEEN BABU with registration Number 201511315 for the award of M.D in the branch of General Medicine I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 2% (TWO percentage) percentage of plagiarism in the dissertation.
Guide & Supervisor sign with Seal
LIST OF ABBREVIATIONS USED
AFI – ASCITIC FLUID INFECTIONS
DCLD – DECOMPENSATED LIVER DISEASE
SBP – SPONTANEOUS BACTERIAL PERITONITIS
MNB – MONO MICROBIAL NUETROCYTIC BACTER
ASCITES
CNNA – CULTURE NEGATIVE NUETROCYTIC ASCITES
CNNNA – CULTURE NEGATIVE NON NUETROCYTIC
ASCITES
HRS – HEPATO RENAL SYNDROME
CTP – CHILD TURCOTTE PUGH SCORE
HE – HEPATIC ENCEPHALOPATHY
MELD – MODEL FOR END- STAGE LIVER DISEASE SCORE
SAAG – SERUM ASCITIC ALBUMIN GRADIENT
PMN – POLYMORPHONUCLEAR NUETROPHILS
LERS – LUECOCYTE ESTERASE REAGENT STRIP KIT
SID – SELECTIVE INTESTINAL DECONTAMINATION
UGI BLEED – UPPER GASTRO INTESTINAL BLEED
NLR – NUETROPHIL-LYMPHOCYTE RATIO
TABLE OF CONTENTS
SL.NO TITLES PAGE.NO
1 INTRODUCTION 1
2 AIMS & OBJECTIVES 3 3 REVIEW OF LITERATURE 4 4 MATERIAL & METHODS 47 5 OBSERVATION AND RESULTS 59
6 DISCUSSION 93
7 CONCLUSION 99
8 BIBLIOGRAPHY 101
9 ANNEXURES
A1.PROFORMA 106
A2.CONSENT FORM 109
A3.KEY TO MASTER CHART 110
A4.MASTER CHART 112
LIST OF TABLES
S.NO TITLES PAGE.NO
1 AGE DISTRIBUTION 60
2 SEX DISTRIBUTION 61
3 HEPATITIS B ETIOLOGY DISTRIBUTION 62
4 HEPATITS C ETIOLOGY DISTRIBUTION 63
5 DISTRIBUTION OF OTHER ETIOLOGIES IN TOTAL 64
6 INDIVIDUAL DISTRIBUTION OF OTHER
ETIOLOGIES
65
7 DISTRIBUTION OF ALCOHOL IN STUDY GROUP 66
8 DISTRIBUTION OF NUETROPHIL-LYMPOCYTIC RATIO IN THE STUDY GROUP
67
9 DISTRIBUTION OF LEUCOCYTE ESTERASE REAGENT STRIP POSITIVITY IN THE GROUP
68
10 DISTRIBUTION OF PURPLE COLOUR AND PINK COLOUR IN LER STRIPS IN THE STUDY GROUP
69
11 CORRELATION BETWEEN NLR AND LER STRIP COLOUR CHANGES IN STUDY GROUP
70
12 CHARACTERISTICS OF LEUCOCYTE ESTERASE STRIPS ACCURACY, PPV, NPV, SENSITIVITY AND SPECIFITY
71
13 PERCENTAGE OF PATIENTS HAVING GROWTH IN THE ASCITIC FLUID CULTURE AND THOSE WHO DON’T HAVE GROWTH
72
14 PERCENTAGE OF INDIVIDUAL BACTERIAL GROWTH IN THE ASCITIC FLUID CULTURE
73
15 PRESENTING COMPLAINTS OF THE PATIENTS SUSPECTED TO HAVE SBP IN THE STUDY
75
16 PERCENTAGE OF PATIENTS IN EACH CHILD TURCOTTE PUGH CLASSIFICATION B AND C
76
17 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND CTP CLASSIFICATION
77
18 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND ABDOMINAL PAIN SYMPTOM
78
19 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND UGI BLEED SYMPTOM
79
20 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND HEPATIC ENCEPHALOPATHY SYMPTOM
80
21 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND DIARRHOEA SYMPTOM
81
22 SIGNIFICANCE OF CORRELATION BETWEEN NLR AND FEVER SYMPTOM
82
23 SIGNIFICANCE OF CORRELATION BETWEEN LER STRIP CHANGES AND CTP CLASSIFICATION
83
24 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND ABDOMINAL PAIN SYMPTOM
84
25 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND UGI BLEED SYMPTOM
85
26 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND HEPATIC
ENCEPHALOPATHY SYMPTOM
86
27 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND DIARRHOEA SYMPTOM
87
28 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND FEVER SYMPTOM
88
29 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND MEAN HB%, MEAN TOTAL COUNT, MEAN NUETROPHIL COUNT, MEAN LYMPHOCYTE COUNT
89
30 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND MEAN HB, MEAN TOTAL COUNT, MEAN NUETROPHIL COUNT, MEAN LYMPHOCYTE COUNT
89
31 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND MEAN SERUM BILIRUBIN, MEAN SGOT, MEAN SGPT, MEAN TOTAL PROTEIN, MEAN TOTAL ALBUMIN, MEAN TOTAL GLOBULIN
90
32 SIGNIFICANCE OF THE CORRELATION BETWEEN
LER STRIP CHANGES AND MEAN SERUM
BILIRUBIN, MEAN SGOT, MEAN SGPT, MEAN TOTAL PROTEIN, MEAN TOTAL ALBUMIN, MEAN TOTAL GLOBULIN
91
33 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND MEAN UREA, MEAN PROTHROMBIN TIME, MEAN INTERNATIONAL NORMALISED RATIO
91
34 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR WITH MEAN TOTAL ASCITIC FLUID CELL COUNT, MEAN TOTAL NUETROPHIL %, MEAN TOTAL LYMPHOCYTE %
91
35 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES WITH MEAN UREA, MEAN PROTHROMBIN TIME, MEAN INTERNATIONAL NORMALIZED RATIO
92
36 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES WITH MEAN TOTAL ASCITIC FLUID CELL COUNT, MEAN TOTAL NUETROHIL %, MEAN LYMPHOCYTE %
92
LIST OF CHARTS
S..NO TITLES PAGE.NO
1 AGE DISTRIBUTION 60
2 SEX DISTRIBUTION 61
3 DISTRIBUTION OF HEPATITIS B ETIOLOGY 62
4 DISTRIBUTION OF HEPATITIS C ETIOLOGY 63
5 DISTRIBUTION OF OTHER ETIOLOGIES 64
6 INDIVIDUAL DISTRIBUTION OF OTHER
ETIOLOGIES
65
7 DISTRIBUTION OF ALCOHOLISM 66
8 DISTRIBUTION OF NLR IN THE STUDY GROUP 67
9 DISTRIBUTION OF LER STRIP POSITIVITY 68
10 DISTRIBUTION OF PURPLE COLOUR AND PINK COLOUR IN THE LER STRIP POSITIVITY GROUP
69
11 CORRELATION BETWEEN NLR AND LER STRIP COLOUR CHANGES
70
12 CHARACTERISTICS OF LER STRIP CHANGES DERIVED FROM THE STUDY
71
13 PERCENTAGE OF PATIENTS WHO HAVE GROWTH IN THE ASCITIC FLUID CULTURE, AND THOSE WHO DON’T
72
14 DISTRIBUTION OF INIDIVIDUAL BACTERIAL GROWTH IN THE CULTURE
74
15 PRESENTING FEATURES OF THE PATIENTS SUSPECTED TO HAVE SBP
75
16 PERCENTAGE OF PATIENTS IN EACH OF CTP CLASSIFICATION CATEOGRY B AND C
76
17 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND CTP CLASSIFICATION
77
18 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND ABDOMINAL PAIN SYMPTOM
78
19 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND UGI BLEED SYMPTOM
79
20 SIGNIFICANCE OF THE CORRELATION BETWEEN
NLR AND HEPATIC ENCEPHALOPATHY
SYMPTOM
80
21 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND DIARRHOEA SYMPTOM
81
22 SIGNIFICANCE OF THE CORRELATION BETWEEN NLR AND FEVER SYMPTOM
82
23 SIGNIFICANCE OF THE CORREALATION
BETWEEN LER STRIP CHANGES AND CTP CLASSIFICATION
83
24 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND ABDOMINAL PAIN SYMPTOM
84
25 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND UGI BLEED SYMPTOM
85
26 SIGNIFICANCE OF THE CORRELATION BETWEEN
LER STRIP CHANGES AND HEPATIC
ENCEPHALOPATHY SYMPTOM
86
27 SIGNIFICANCE OF THE CORREALATION
BETWEEN LER STRIP CHANGES AND
DIARRHEOA SYMPTOM
87
28 SIGNIFICANCE OF THE CORRELATION BETWEEN LER STRIP CHANGES AND FEVER SYMPTOM
88
1
INTRODUCTION
Spontaneous bacterial peritonitis is a potentially lethal complication of cirrhotic ascitis, with the prevalence of 10%-30% among hospitalized cirrhotic patients. Although early recognition and initiation of antibiotics produces satisfactory response in most cases, the mortality remains high as 30%-60%.
Improved survival in SBP can be achieved by rapid diagnosis and prompt initiation of treatment. Ascitic fluid infection primarily consists of two variants- Spontaneous Bacterial Peritonitis and Culture Negative Neutrocytic Ascites.
Presence of more than 250 polymorphonuclear leukocytes per micro litre of ascitic fluid is considered as a surrogate marker for diagnosing SBP, irrespective of the culture report and to initate therapy. Symptoms and signs of SBP are frequently absent in patients with SBP, hence a diagnostic paracentesis should be performed on a clinical suspicion. However access for quick total and differential leukocyte count may not be readily available at all times, so availability of a rapid bedside screening test will help in the early diagnosis of SBP and reduce the morbidity and mortality associated with it. Leukocyte esterase reagent strip can be easily used in the bed side to diagnose spontaneous bacterial peritonitis as a cheap indicator of inflammation and sepsis and also in various traumatic, tumours and surgical conditions. So the aim of the study is to analyse whether leukocyte esterase reagent strip can be used to detect bacterial peritonitis in the bed side and whether it will aid in the early
2
detection and initiation of empirical antibiotic therapy by comparing it with Nuetrophil-Lymphocytic ratio of the ascitic fluid so that these strips can be used to prevent mortality and morbidity in cirrhotic patients.
KEY WORDS: Ascitic fluid infection, Spontaneous bacterial peritonitis, Leukocyte Esterase reagent strip (LER), Cirrhosis, Inflammation, NUETROPHIL-LYMPHOCYTIC ratio (NLR), Portal hypertension, Hepatic encephalopathy, Hepatitis-B, Hepatitis-C, Non alcoholic fatty steato-hepatitis, Cryptogenic cirrhosis, Alcoholic liver disease, Hepato cellular carcinoma, Wilson”s disease, Haemochromatosis, Serum ascitic albumin gradient.
3
AIMS & OBJECTIVES
1. Is to find out the diagnostic ability of the leukocyte esterase reagent strip in the bedside of the patients suffering from spontaneous bacterial peritonitis due to decompensated cirrhotic liver disease with ascites so that early diagnosis is made and empirical antibiotic started so that morbidity and mortality can be reduced.
2. The Objective is to find out the Leukocyte Esterase Strip analysis accuracy in the spontaneous bacterial peritonitis in comparison with neutrophil-lymphocytic ratio of the infected ascitic fluid.
3. To study the Incidence and Prevalence of Ascitic Fluid Infections (AFIs) in Cirrhotic patients of various etiologies.
4. To detect the common pathogen”s prevalence of Ascitic Fluid Infections (AFIs) in patients with Cirrhosis.
5. To Establish whether bedside strip tests are equally efficacious to that of the Nuetrophil-Lymphocytic Ratio of ascitic fluid along with the ascitic fluid culture growth in establishing ascitic fluid infections.
6. To study the microbial spectrum of Ascitic Fluid Infections (AFIs) in patients with DCLD.
4
REVIEW OF LITERATURE INTRODUCTION
Ascites refers to excessive pathologic accumulation of fluid in Peritoneal cavity. The most common cause of ascites is CIRRHOSIS WITH PORTAL HYPERTENSION (85%) whichoccurs in 50% within 10 years of diagnosing cirrhosis. The development of ascites denotes the patient progress to decompensated cirrhosis. Other complications are variceal hemorrhage, hepatic encephalopathy and jaundice; Ascites is the most common. It is due to factors involving the peritoneum (malignancy), infection, or diseases away from the peritoneum, heart failure, hypoproteinaemia, liver disease. Cirrhosis is the most important causative agent of ascites in the West (76%), followed by peritoneal malignancy (14%), cardiac failure (5%) and peritoneal tuberculosis (4%). Cirrhosis is a linguistic disorder with indolent course and many patients will be asymptomatic until decompensation. Early and well compensated cirrhosis usually presents as loss of apetite and weight loss, malaise, fatigue and weakness. Decompensated Liver Disease is an end stage liver disorder with liver fibrosis and with complications like ascites, variceal bleeding, hepatic encephalopathy, reduced metabolism and enzyme production and hepato pulmonary syndrome. DCLD patients have a poor prognosis and their 1-year and 5-year survival rates of 80% and 56% respectively. Cirrhosis is an immune-suppressed status where both cell mediated and humoral immunity are decreased. These patients have reduced serum bactericidal opsonins,
5
complements (C3,C4), protein C and fibronectin . There is local and systemic immune dysfunction. Owing to porto-systemic shunting bacteria and bacterial endotoxins are not cleared by liver from portal circulation. This predisposes patients to lot of infections . This is later complicated by alcohol consumption, malnutrition, invasive procedures, catheters, immunomodulatory status.
DCLD is associated with increased susceptibility to infections. Bacterial infections takes for 37%-57% of deaths in these patients. Nosocomial infections have a rate of 30%-32% and may be up to 49% with variceal bleeding. The most common bacterial infections in the descending order of frequency are Spontaneous bacterial peritonitis (SBP) (15-30%), Urinary tract infections (25-29%), pneumonia (18-22%), bacteremia (17%) and soft tissue infection (15%). Gastrointestinal variceal hemorrhage is accompanied with infection in 60% of cirrhotics due to disruption of intestinal mucosal barrier and invasive procedures during bleeding. Infection triggers cytokine pathway with release of vasoactive mediators which causes increased variceal pressure, disordered homeostasis leading to further variceal bleeding. Infections are most common if there is failure to control gastrointestinal bleeding within 120 hours and associated with early rebleeding rate. Antibiotic prophylaxis prevented infection and episodes of rebleeding and also the need for blood transfusion. The prevalence of this condition in those hospitalized with DCLD is 10-37% with 28% of those with hepatic encephalopathy. The recurrence rate after first SBP episode is 41% at 5months, 63% at 1 year and 72% at two years
6
and sensible prophylaxis can reduce the recurrence rate to 25%. The frequency of ascitic fluid infection among outpatients is as low as 0-3.7%. The in-patient mortality varies from 2245%, with mortality rate of 57-72% at one year of follow up. Serum creatinine levels >1.5 mg/dl with lab culture were good predictors of mortality. The progress of underlying liver disease is difficult to control and hence early detection and timely precise management of infections can improve the outcome. AFIs are under diagnosed by conventional culture methods since the median bacterial concentration is only approximately 1-2 organisms per millilitre. Hence, this study was done to detect Ascitic Fluid Infections (AFIs) in patients with Decompensated Liver Disease (DCLD), by bedside inoculation of ascitic fluid in leukocyte esterase ascitic fluid strip test. This could increase diagnosing infection at earlier time, facilitate rapid isolation of organisms and help to administer appropriate antimicrobial therapy at the earliest.
ANATOMY OF LIVER:
7 FUNCTIONAL SEGMENTS OF LIVER:
PORTAL TRIAD:
8 BLOOD SUPPLY TO THE LIVER:
Cirrhosis means a non remitting progressive, diffuse, fibrotic and nodular regeneration of liver so that the liver architecture is disrupted. Long standing injury to the liver can proceed on to insult the liver to cause cirrhosis.
There is persistent wound healing resulting in fibrosis.80-90% of the liver parenchyma must be destroyed for liver dysfunction to exhibit clinically.
Cirrhosis is a indolent disease with silent course and many patients remain symptom free until they reach decompensation. Alcoholic liver disease (ALD) is an important risk factor for cirrhosis. Individuals who consume large amounts of alcohol for prolonged period (about >64-84grams/day in males and
>22grams/day in females over 11 years or longer) progress beyond the stage of
9
steatosis of liver (92%) to develop alcoholic hepatitis and fibrosis (12-37%) then to cirrhosis (5-18%). Women are more prone to develop Alcoholic liver disease within shorter life span due to increased activity of alcohol dehydrogenase activity in the gastric mucosa and liver and they have a lean body mass different from men and lower threshold toxic dose. This has been attributed to the gender dependent differences in the hepatic metabolism of alcohol. The complications of liver disease are due to impaired hepatic function and disruption of the normal hepatic architecture.
FLUID RETENTION IN CIRRHOSIS
Ascites is a greek term (askes) which refers to a bag/sac. In cirrhotic patients there is more formation of vasoconstrictors which leads to increased vascular tone. There is distortion of architecture of the liver. Both these lead to portal hypertension (sinusoidal). This portal hypertension activates vasodilatory mechanisms. There is increased production of nitric oxide (NO) which leads to splanchnic and peripheral arterial vasodilation. This later causes decreased levelling of systemic vasculature and drop in pressure. This causes baroreceptor induced activation of renin pathway with increased activity of sympathetic drive and arginine vasopressin .These events lead to renal sodium and water retention to restore normal homeostasis. Also, splanchnic vasodilation leads to increased lymph production and leakage into peritoneal cavity. Both the events lead to sustained ascites formation.
10
CLASSIFICATION OF ASCITES-THE INTERNATIONAL ASCITES CLUB
Grade one : Ultrasound detected.
Grade two : Abdominal distension.
Grade three : Tense Ascites
Ascites (Uncomplicated): Infection/HRS absent.
Refractory ascites: prevention with drug treatment after therapeutic paracentesis.
Diuretic resistant ascites: high dose / maximum dose of diuretic treatment.
Diuretic-intractable ascites : diuretics causing side effects leading to improper treatment.
DIFFERENTIAL DIAGNOSIS OF ASCITES
CIRRHOSIS-85%
OTHERS-15%
Alcoholic hepatitis
Cancer (peritoneal carcinomatosis, massive liver metastases, etc)
“Mixed” ascites, i. e., cirrhosis plus another cause for ascites
Pancreatitis
Nephrotic syndrome
11
Tuberculous peritonitis
Heart failure
Acute liver failure
Budd-Chiari syndrome
Postoperative lymphatic leak Sinusoidal obstruction syndrome
Myxedema
Primary biliary cirrhosis
Primary sclerosing cholangitis
Haemochromatosis
Wilson’s disease
Chronic active hepatitis
Alpha 1-antitrypsin deficiency
Nonalcoholic steatohepatitis
Cryptogenic cirrhosis
Autoimmune hepatitis
Viral infections-Hepatitis B, Hepatitis C
Autoimmune cholangiopathy
12 HISTORY
It is of historical interest that Ludwig von Beethoven is probably the first patient known by name to have had SBP, especially since the clinical description of his case had been written 135 years before this syndrome was first described. Kerr et al & Conn, printed papers which explained ascitic fluid infections (AFIs) in the absence of contiguous or intra-abdominal source of infection.
In 1964, Conn was the one who coined the term Spontaneous bacterial peritonitis (SBP).
Runyon who has done several works in SBP suggests we now drop the term “SPONTANEOUS” since the pathogenesis has been studied and worked out.
ALCOHOLIC LIVER DISEASE
Alcoholic Liver Disease (ALD) is the most important risk factor for the development of cirrhosis. Individuals who consume large quantity of alcohol for prolonged period, about 60-80gm/day in males and >20gm/day in females over 10 years or longer progress to steatosis of liver in 92% of people. Steatosis can progress to alcoholic hepatitis in 12-37% of people and to cirrhosis in 5-18% of people.
13
Women are more prone to develop Alcoholic liver disease in a short lifespan due to decreased activity of alcohol dehydrogenase in gastric mucosa and in the liver. Also women have a lean body mass and low threshold for toxic dose when compared to men. This has been attributed to the gender dependent differences in the hepatic metabolism of alcohol.
COMPLICATIONS OF CIRRHOSIS 1. Portal hypertension
i) Gastro esophageal varices ii) Portal hypertensive gastropathy iii) Splenomegaly
iv) Ascites
v) Spontaneous bacterial peritonitis 2. Hepato renal syndrome
3. Hepato pulmonary syndrome 4. Hepatic encephalopathy 5. Porto pulmonary hypertension 6. Malnutrition
7. Coagulopathies 8. Bone disease
14 9. Haematological abnormalities
i. Anaemia ii. Hemolysis iii. Nuetropenia
iv. Thrombocytopenia
ASCITES:
Defined as pathological accumulation of fluid in the peritoneal cavity.
The most recent theory for the formation of ascitic fluid is “The peripheral arterial vasodilation hypothesis”. The older theories are Underfilling and overfilling theory.
PATHOGENESIS OF ASCITES
In cirrhotic patients the changes in portal flow and resistance are due to mechanical and vascular factors.
Mechanical factors include the fibrosis and nodularity with distortion of the vascular architecture and the remodelling of the cirrhotic liver.
Vascular factors include intra hepatic vasoconstriction, due to increased production of vasoconstrictors like Endothelin-1 which contributes to increased intrahepatic resistance. Both these leads to PORTAL (SINUSOIDAL) HYPERTENSION.
15
This portal hypertension activates vasodilatory mechanisms. There is increased production of nitric oxide (NO) in the splanchnic circulation which leads to splanchnic and peripheral arterial vasodilation. The later causes decreased levelling of systemic vasculature and produces drop in systemic pressure.
The fall in systemic pressure causes baroreceptor- induced activation of renin- angiotensin pathway with increased activity of sympathetic system and arginine vasopressin mechanism. This results in renal sodium and water retention to maintain normal homeostasis. Also, splanchnic vasodilation leads to increased lymph production and leakage into peritoneal cavity. Both these events lead to sustained ascitic fluid formation.
CAUSES OF ASCITES
Hepatitis B
Hepatitis C
alcoholic liver disease
cryptogenic cirrhosis
primary biliary cirrhosis
Non alcoholic fatty steatohepatitis
hepatocellular carcinoma
acute liver failure
16
paracetamol poisoning
vinyl chloride toxicity
Wilson’s disease
THE PATHOGENESIS OF ASCITES EXPLAINED:
THE UNDERFILL THEORY OF ASCITES EXPLAINED:
17 MIXED ASCITES
Have underlying portal hypertension with cirrhosis along with other conditions like TB or peritoneal carcinomatosis.
SECONDARY PERITONITIS Look for it when:
1. No diminish in ascitic fluid PMN count 48 hours after antibiotic starting.
2. Two or more organisms shown on culture 3. If in ascitic fluid atleast two (2/3) is seen:
AF protein >1g/dl.
AF lactate dehydrogenase (LDH)>225mU/ml.
AF glucose <50 mg/dl.
Antibiotics against anaerobes and enterococci have to be added.
TUBERCULOUS PERITONITIS
Abdominal tuberculosis, the sixth most frequent siteof tuberculosis.
Peritoneal TB occurs in three types:
1. Fibrotic type.
2. Encysted (loculated) type.
3. Wet type with ascites.
Macroscopically it is straw coloured and an exudate (protein>3g/L).
18
The total cell count is 500-2000 cells/mm3 with predominant of lymphocytes. Lymphocytosis of ascitic fluid means that the lymphocytes account for >30% of total AF cell count.
Sometimes PMN”s may be abundant (>250/mm3) early in the disease and this can lead to misdiagnosis as SBP.
The SAAG has a gradient of <1.1g/dl.
The adenosine deaminase (ADA) of >33U/L has a sensitivity of 98%
and specificity of 100% in non-cirrhotic patients.
The yield of tubercle bacilli on smear and culture is low and large amounts of fluid (about 1L) has to be used for centrifugation and the deposit is inoculated on LJ medium. The time taken for growth of tubercle bacilli is usually 6-8 Weeks.
ASCITIC FLUID INFECTIONS (AFI).
The most common complication of cirrhosis with portal hypertension is the ascitic fluid infection (31%) .
Ascitic fluid infections (AFIs) has been classified into five variants based on analysis of the following parameters-
• Polymorphonuclear leukocyte (PMN) count
• Culture growth and
• Mode of entry of organism into the fluid.
19
CLASSIFICATION OF ASCITIC FLID INFECTION 1. Spontaneous Bacterial Peritonitis
2. Monomicrobial Non-Neutrocytic Ascites 3. Culture Negative Neutrocytic Ascites 4. Polymicrobial Bacterascites
5. Secondary Bacterial Peritonitis
Criteria for diagnosing Spontaneous Bacterial Peritonitis 1. PMN count >250cells/mm3.
2. A positive ascitic fluid culture.
Criteria for diagnosing Monomicrobial Non-Neutrocytic Ascites 1. PMN count < 250cells/mm3.
2. A positive ascitic fluid culture for a single organism.
Criteria for diagnosing Culture Negative Neutrocytic Ascites 1. PMN count is 250cells/mm3.
2. Ascitic fluid culture - no organism
Criteria for diagnosing Polymicrobial Bacterascites 1. PMN count < 250cells/mm3.
2. Ascitic fluid culture – multiple organisms
20
Criteria for diagnosing Secondary Bacterial Peritonitis 1. PMN count is 250cells/mm3.
2. Ascitic fluid culture – multiple organisms
3. Intra abdominal surgically treatable primary infection
PATHOGENESIS GENERAL CONCEPT
In cirrhosis bacterial overgrowth results from the migration of microbes from the intestinal lumen into mesenteric nodes and into the systemic circulation and other extra-intestinal sites since they pass through the liver and increased majority of portal flow diverts away from the liver sinusoids. This persistent bacteremia leads to ascitic fluid infection since it is an excellent bacterial culture medium.
BACTERIAL OVERGROWTH
WHAT ARE THE POSSIBLE ROUTES BY WHICH BACTERIA MAY ENTER THE PERITONEUM?
Organisms can come directly from the gastrointestinal tract, from the blood stream. The rarest route is through the Fallopian tubes. This route of entry has been implicated by McCartney to explain the predominance of girls with primary peritonitis.
21
The most common causes of bacterial peritonitis were perforations of ulcers of the upper gastrointestinal tract or the rupture of abdominal viscera, usually the appendix. Although perforations of the gastrointestinal tract may be silent clinically, they are rarely so, and even when silent they usually exhibit pneumoperitoneum. Under certain conditions bacteria may enter the peritoneal cavity by traversing the intact intestinal wall.
Bacterial overgrowth occurs from the overgrowth of a single species of indigenous bacteria in the intestinal tract, immunosuppression, and thermal injury in which large segments of skin are burned, to hemorrhagic, hypotensive shock, i.e., insufficient blood supply to the gastrointestinal (GI) tract. In addition, specific disorders of the GI tract, such as intestinal or biliary obstruction or portal hypertension, may all give rise to Bacterial overgrowth.
It is possible that the hepatic lymphatics themselves may be involved in the pathogenesis of this syndrome. Hepatic lymph is the key to the formation of ascites. In cirrhotic patients with hepatic venous outflow obstruction the production of hepatic lymph is increased resulting in the formation of ascites, due largely to the exudation of hepatic lymph directly into the peritoneal cavity.
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II. WHAT ARE THE FACTORS THAT RENDER CIRRHOTIC PATIENTS PARTICULARLY PRONE TO DEVELOP SPONTANEOUS PERITONITIS?
Failure of hepatic removal of bacteria from the blood stream. McIndoe described the extrahepatic portal-systemic collateral networks that shunt portal venous blood around the liver. Such portal-systemic shunts have been shown to diminish greatly the hepatic clearance of ammonia and other substances absorbed from the gastrointestinal tract. Presumably, these portal-systemic anastomoses permit circulating bacteria to bypass the hepatic reticuloendothelial filtering system, which has been shown to be the major site of removal of bacteria from the blood. Decreased hepatic removal of circulating bacteria tends to perpetuate bacteremia and thus afford circulating organisms a greater opportunity to cause metastatic infections at susceptible sites such as ascitic collections.
Normally the portal venous blood is aseptic. In case of migration of bacteria from infected lumen, they are getting trapped and removed by the liver. Cirrhotics have increased and abnormal bowel flora. Bacterial overgrowth is increased in cirrhosis by delayed intestinal transit, decreased luminal IgA and bile salts.
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Normal distal movements of luminal contents by peristalsis helps to avoid bacterial colonization and multiplication in the upper intestine. The complete or partial absence of the phase III activity of MMC (MIGRATORY MOTOR COMPLEX)- the “intestinal housekeeper” results in overgrowth.
In cirrhosis, there is increase in bacterial colonization of the small bowel (31-53%) with bacteria from the large bowel.
INTESTINAL MUCOSAL BARRIER SECRETORY (1st DEFENCE) MECHANISM
The intestinal goblet epithelial cells secrets mucins the electro negative charged layer prevent direct contact between bacteria and intestinal membrane.
In cirrhotics there is elevated permeability of mucosa (patients with sepsis) due to oxidative stress, elevated Nitric Oxide and, endotoxemia, proinflammatory cytokine, enterocyte mitochondria malfunction .
IMMUNOGLOBULIN A
70% of body’s immunoglobulin production is IgA. In cirrhotics there is diminished mucosal IgA.
BILE’s TROPHIC EFFECT
Bile inhibits intestinal bacterial overgrowth; bile has detergent action and anti-adherence properties, endotoxin removal action, trophic effect for intestinal mucosa with decreased epithelial bacteria internalisation. The
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quantity of bile acids in liver disease is diminished due to decreased secretion and accentuated deconjugation of intestinal flora. It aids bacterial translocation caused by endotoxins.
THE PHYSICAL(2nd line of DEFENCE) MECHANISM Intestinal Epithelial Structure
Tight junctions between the cells located at the apico lateral surface of the epithelium inhibits bacterial or liopolysacchride transport. In liver disease there is intercellular spaces widening, diminished crypts and villus, Vasodilation, muscularis mucosae involovement, Oedema, and fibromuscular proliferation all dislodge the integrity of the normal epithelium.
NATURAL ANTIBIOTICS SECRETION
Paneth cells in the jejunal crypts and ileal crypts produce phospholipase A2, defensins, and lysozyme, cryptidin related signal peptides, Angiogenin.
Small intestine epithelial cells and Colonic epithelial cells secrete – defensins that defend against commensal bacteria. In chronic liver disease secretion of these substances with antimicrobial activity is reduced.
GUT ASSOCIATED LYMPHOID TISSUE.
Four components
Lymphocytes from the lamina propria.
Intraepithelial lymphocytes
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Mesentric lymph nodes(MLN)
Peyer’s patches
When the Bacteria interact with the structures in the Gut associated T lymphocytes there is multiplication of lymphocytes, germinal center appear in the follicles and mucosal immunoglobulin secretion elevated . The primary immune response is associated with monocytes,
By its interaction with PRR-PATTERN RECOGNITION RECEPTOR with specific bacterial ligands PAMPs- PATHOGEN ASSOCIATED MOLECULAR PATTERNS, Antigens are taken up by the dendritic cells through the local antigen presenting cells (APCs)-DIRECT MECHANISM and by M cells which overtake antigen by endocytosis - IN DIRECT MECHANISM.
Microbial peptides are presented by the Antigen presenting cells to the B & T lymphocytes. This will reach a climax in secretion of mucosal IgA(or IgG) or transformation into Th1 and Th2 cells. On exposure to the antigen, the T lymphocyte from the Peyer’s patchesmove towards lamina propria and gets tranformed into CD8 cytotoxic T lymphocytes. Impaired primary and adaptive immune response occurs in DCLD.
26 BACTERIAL TRANSLOCATION
Portal hypertension causes venous stasis, hypoxia of the mucosa and oxidative stress damage. This leads to splanchnic dilatation with Mucosal congestion and Bowel Oedema leading to altered permeability and bacterial translocation to mesentric lymph nodes. Gram negative bacteria are more prone than gram positives and anaerobes for translocation. Bacteria generally do not migrate directly from the lumen into ascitic fluid. It happens if there is loss of mucosal integrity. Anaerobes are present in excess in gut flora which translocate only in intestinal mechanical injury and are occasionally isolated from ascitic fluid in SBP. More virulent organisms and Escherichia coli strains with greater adherence to intestinal mucosa translocate more precisely.
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INVASION OF ASCITIC FLUID AND BACTEREMIA
There is splanchnic and systemic vascular dilatation along with the formation of hyperdynamic circulatory state with elevated cardiac output and drop in blood pressure. Bacteremia leads to spill over of the organisms from mesenteric lymph nodes into systemic circulation.
Due to the diminished phagocytosis of reticuloendothelial system, the bacteria stays uncleared from the circulation. In cirrhotics, there are intra and extra hepatic shunts and because of it the bacteria never come into alignment with the Kupffer cells and the bacteremia increases. Bacteremia leads to colonisation of ascitic fluid as the infected fluid oozes off of the Glisson’s capsule or when infected interstitial fluid oozes from the intestinal capillary bed.
SBP AND BACTERASCITES
Opsonins level and C3 complement are decreased in DCLD. Low protein concentration (<1g/dl) has a positive correlation with decreased opsonic activity. Opsonins and macrophage were not able to kill the bacteria and so neutrophils are allowed to do the killing. SBP occurs, since there is impaired neutrophil function or qualitative neutrophil abnormalities.
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SEPSIS AND SYSTEMIC INFLAMMATORY RESPONSE SYNDROME Molecular evidence of bacterial translocation is given by Identifying the DNA of the bacteria in the body fluid. Lipopolysaccharides and peptidoglycans in the bacteria can trigger the TLR (T LYMPHOCYTE RECEPTORS) receptorsthat leads to the production of pro-inflammatory cytokines. This leads to increased release of tumor Cytokines that leads to inadequate tissue perfusion, multi- organ failure and death, refractory hypotension, sepsis syndrome pathways.
ASCITIC FLUID INFECTIONS(AFI).
Is the most frequent (31%) of all infections among cirrhosis with portal hypertension. Ascitic fluid infections(AFIs) has been classified into five variants based on analysis of the following parameters- Polymorphonuclear leukocyte (PMN) count, culture growth and mode of entry of organism into the fluid.
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ASCITIC FLUID INFECTIONS VARIANTS VARIANTS OFASCITIC FLUID
INFECTIONS(AFIs)
PMNCOUNT Cells/mm3
CULTURE GROWTH Spontaneous bacterial
peritonitis(SBP) •250 Monomicrobial
Culture-negative neutrocytic ascites (CNNA)
•250 No growth
Monomicrobial nonneutrocytic
bacterascites (MNB) <250 Monomicrobial Secondary bacterial peritonitis-
Indicates surgical cause such as perforated viscus/intra-abdominal
abscess.
•250 Polymicrobial
Poly microbial bacterascites- Perforation of the bowel by
paracentesis needle.
<250 Polymicrobial
HEPATORENAL SYNDROME
The Annual incidence of HRS in patients with ascites is 10%. There is no major change in renal biopsy and is completely relieved by liver transplantation. This is mainly due to the decreased effective circulating volume and increased levels of vasodialators like nitric oxide.
The increased cardiac output and increased plasma volume as a compensatory increase are not sufficient in amount to restore the decreased
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effective circulating volume, the renin-angiotensin mechanism is activated leading further activation of other vasoconstrictor mechanisms leading to sodium and water retention and ascites formation. Impaired immune mechanisms in portal hypertension and intestinal epithelial barrier dysfunction cause the translocation of bacteria and lead to infection of ascitic fluid causing spontaneous bacterial peritonitis and further aggravation of the cycle leading to worsening of hepato-renal syndrome.
THE PATHOGENESIS OF HEPATO RENAL FAILURE EXPLAINED:
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NEW DIAGNOSTIC CRITERIA OF THE HEPATORENAL SYNDROME
Cirrhosis with ascites
Serum creatinine >1.5 mg/dL (133 micromol/L)
No improvement of serum creatinine (decrease to a level of 1.5 mg/dL or less) after at least 2 days of diuretic withdrawal and volume expansion with albumin.
The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria of >500 mg/day, micro hematuria (>50 red blood cells per high power field), and/or abnormal renal ultrasonography
Adapted from Salerno et al.
HEPATORENAL SYNDROME TYPE 1
Renal failure with increased serum creatinine reaching more than 2.5 mg/dl in <2 weeks. May occur spontaneously or in can be precipitated by bacterial infections, gastrointestinal haemorrhage or acute hepatitis superimposed on cirrhosis. Develops in 30% of inpatients with SBP.
32 HEPATORENAL SYDROME TYPE 2
Moderate and steady decrease in renal function over months (serum creatinine < 2.5 mg/dl). There is severe ascites with poor or no response to diuretics (refractory ascites).
CHILD TURCOTTE PUGH (CTP) SCORE
Initially used to prognosticate the short term mortality, it is now used to assess the prognosis and the requirement for liver transplantation. It contains parameters like ascites and hepatic encephalopathy.
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MODEL FOR END STAGE LIVER DISEASE SCORE (MELD SCORE) Includes three lab objectives international normalized ratio (INR), serum creatinine and serum bilirubin. MELD=9.57 × log e (creatinine)+3.78×log e (total bilirubin) +11.2 × log e (INR) + 6.43.
MELD is better than CTP in evaluating the mortality following variceal bleeding. Addition of the creatinine which measures the renal function, explaining its importance in evaluation of mortality risk. CTP has more variability than MELD. Also MELD has wider possible scores and offers more weightage than CTP. Patients with high MELD score (>5) are more prone for infections and mortality than patients with low MELD score (<15).
PREDISPOSING AGENTS FOR ASCITIC FLUID CONTAMINATION IN DCLD
Severity of the liver disease-Child-Pugh class C patients
Urinary tract infection and asymptomatic bacteruria
Serum total bilirubin level MORE THAN 2.5 mg/dl
Gastrointestinal bleeding
Low platelet count(<80,000/mm3)
Increased prothrombin time
Increased liver enzymes
Previous episodes of SBP
Ascitic fluid protein level <1g/dl and complement C3 <13 mg/dl
High creatinine and blood urea nitrogen
34 SIGNS AND SYMPTOMS
The most common reported are:
Fever (78%)
Abdominal pain (68%)
Hepatic encephalopathy (43%)
Ileus or Diarrheoa (21%)
Vomiting (20%)
About 14% of patients with SBP are asymptomatic.
RECOMMENDATIONS FOR DIAGNOSIS OF AFIs.
The AFIs clinically presents with single or multiple symptoms.
Considerable elapse of time leads to raised morbidity and mortality. The diagnosis is primarily on ascitic fluid analysis.
Attempting to correct coagulopathy is not needed and is not cost Evading.
DIAGNOSTIC PARACENTESIS 1. New onset ascites
2. Localising signs of peritonitis mentioned above 3. At the time of each admission to hospital
4. In gastrointestinal bleeding prior to antibiotic prophylaxis.
5. Any other laboratory test abnormalities 6. Rapid impairment renal function
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7. Paracentesis is safe despite the predictable coagulopathy in cirrhotic patients.
8. The risk of complication is negligible-prolonged leakage (m/c) (2%), chance of abdominal wall haematoma (0.02%), chance of haemo peritoneum (0.02%), chance of iatrogenic infections (0.7%) and visceral perforation. This clearly outways the benefits.
ASCITIC FLUID LABORATORY TESTS DATA
TESTS TO BE DONE FOR DIAGNOSIS OF AFIs 1. Cell counts with differential counts
2. Culture (in blood culture bottles) 3. Gram’s stain
4. Total protein
5. Lactate dehydrogenase
ROUTINE OPTIONAL UNUSUAL UNHELPFUL Cell count and
differential
Culture in blood culture bottles
AFB smear
&culture
PH
Total protein Gram’s stain Cytology Lactate
Albumin
Glucose Triglyceride Fibronectin Amylase
Bilirubin
Cholesterol Lactate
dehydrogenase Glycosaminoglycans
36 6. Glucose
7. Amylase
8. Albumin (to calculate SAAG)
9. SAAG = Serum-ascites albumin gradient.
10. These tests also help to readily differentiate and identify the various etiologies of ascites besides from portal hypertension.
11. The SAAG (Serum-ascites albumin gradient) helps in delineating ascites better than the total protein based (transudate/exudate) criteria.
CORRECTED SAAG
In serum hyperglobulinemia (>5g/dl), narrow SAAG gradient occurs in 1% of ascitic fluid specimen.
CORRECTED SAAG = UNCORRECTED SAAG × 0.16 × (SERUM GLOBULIN [G/DL] + 2.5)
MIXED ASCITES
Have underlying portal hypertension with cirrhosis along with other conditions like TB or peritoneal carcinomatosis. SAAG was more, due to underlying portal hypertension.
MACROSCOPY: GROSS APPEARANCE 1. Crystal clear- protein level decreased
2. Transparent and yellow-Non-neutrocytic ascites (PMN<250/mm3)
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3. Cloudy-Cell value of 5000/mm3 is cloudy, and greater than 50,000/mm3 appears mayonnaise.
4. Bloody- Ascitic Fluid red blood cells of 10,000/mm3 is the maximum value. more than 20,000/mm3 is always red. Seen in 50% of cases with cirrhosis and hepatocellular carcinoma.
5. Chylous / Milky-Ascitic Fluid with triglyceride content>200 mg/dl, found in malignancy-related ascites and in about 21% of cirrhotic ascites.
6. Dark brown-Biliary concentration more than that of serum, due to biliary perforation.
IMPORTANCE OF CELL COUNT
The ascitic fluid POLYMORHO NUCLEAR LEUKOCYTES count (maximum> two fifty cells/mm3) is the efficient test for diagnosis of AFI. But PMN count above this value can also be found in bleeding into ascites, peritoneal carcinomatosis and pancreatic ascites.
In tuberculous or malignant ascites, lymphocytes increase.
HAEMORRHAGIC ASCITES =CORRECTION FACTOR
Accurate PMN count can be calculated only in non-traumatic tap.
Haemorrhagic fluid can occur in severe coagulopathy or in bloody tap (or)
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malignant ascites. Correction factor to be applied by deducting one neutrophil for every 250 rbc cells/mm3.
MANUAL VS AUTOMATED COUNTING
The laboratory should perform the cell count within 60 minutes. The manual count is error-prone and subjective and it also retards the start of ever needed empirical antibiotic therapy and yet still used and preferred.
Automated cell counters are ideal but the manufacturers do not recommend it for fluids other than blood. This can be useful if further validated.
ASCITIC LEUKOCYTE ESTERASE REAGENT (LERS) STRIPS
Leukocyte esterase is an intracellular enzyme within the PMNs and is released upon lysis of PMNs during inflammatory cascade. The strip is placed inside a test tube of fresh ascitic fluid at the bedside and kept for 90 seconds.
The esterase present in the PMNs act on the ester substrate and releases 3- hydroxy-5-phenyl-pyrrole. This changes the color of an azo dye in the reagent strip. The calorimetric scale reference chart is available for direct optical comparison on the sides of the container.
See for the purple colour on the strips which is equivalent to a PMN count of greater than 250/mm3 so that first dose of empiric antibiotic can be
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given (reduces the tap-to-shot time). It is faster and cheaper rapid . Example:
NEPHUR TEST KIT.
SECONDARY PERITONITIS
Look for it when:
1. No diminish in ascitic fluid PMN count 48 hours after antibioticstarting.
2. Two or more organisms shown on culture (esp fungus or anaerobes).
3. If in ascitic fluid atleast two (2/3) is seen -- AF protein >1g/dl.
-- AF lactate dehydrogenase (LDH)>225mU/ml (normal serum level).
-- AF glucose <50 mg/dl.
RELAVENT ADDITIONAL INVESTIGATIONS
1. Blood cultures associated with the ascitic fluid cultures-positive in atleast 1/3 rd of cases.
2. Complete blood count
3. WBC count may be low inspite of the presence of SBP due to Hypersplenism.
4. Urine analysis and urine culture - asymptomatic bacteriuria is an independent risk factor.
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5. Liver function tests-Total and direct bilirubin, liver enzymes AST, ALT, SAP, GGT, Total protein and albumin, globulin.
6. Cefotaxime 2g every 12 hr for 7 days is the common empiric antibiotic. Second ascitic tap done 48 hrs after start of therapy and there should be a 30% decrease in cell count. Otherwise change the antibiotic.
CAUS ES OF LOW GRADIENT (SAAG <1.1g/dl) ASCITES 1. TB-AF LDH (<250 U/ml) and glucose level lower 2. Pancreatic ascites
3. Malignancy induced ascites-AF LDH and glucose level higher 4. Biliary ascites
5. Renal ascites
SELECTIVE INTESTINAL DECONTAMINATION (SID) Norfloxacin is recommended :
Poor intestinal absorption and rapidly diffusion into ascitic fluid.
Preserves anaerobes and prevents gut colonization by pathogenic bacteria.
Strong activity against gram negative bacteria.
Has fewer side effects.
Should be started in Patients with gastrointestinal bleeding, Norfloxacin 400 mg BD × 7days (SHORT TERM).
AF protein level <1.5g/dl
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Patients who have recovered from previous SBP, Newer quinolones are preferred since apart from eliminating gram negative bacteria, they also decrease bacterial adhesion to mucosa, and they also stimulate bactericidal capacity of PMNs.
Patients who survive an episode of SBP have 41 to 71% chance of relapse in the coming 13 months. Hence, long term administration of quinolones is advocated for these patients till symptoms and signs of ascites resides, transplantation or death. But because of approach there is trending towards infections caused by GRAM POSITIVE COCCI. For patients on quinolone prophylaxis who develop an SBP episode, third generation cephalosporins are the best option.
MICROBIOLOGY
Bacteria most commonly isolated from ascitic fluid in patients with SBP are usually those of the normal intestinal flora. More than 92% of all cases are monomicrobial with aerobic gram negative bacilli. This is being responsible for more than two third of cases.
Escherichia coli accounts for nearly half of these cases followed by Klebsiella spp and other gram negative bacteria. Twenty-five percent of cases are caused by gram positive organisms with Streptococcus pneumoniae and viridans being the most common. In bacterial peritonitis associated peritoneal carcinomatosis, the microorganisms isolated are those which are not usually
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known to cause SBP and quite virulent, for example, Salmonella spp. SBP is rarely caused by anaerobic organisms, so their presence in ascitic fluid should raise suspicion due to some other cause. In other cases, the bacteria may reach the ascitic fluid from the urinary or respiratory tracts.
COMMON PATHOGENS INVOLVED IN ASCITIC FLUID INFECTION
1. Escherichia coli
2. Klebsiella pneumoniae 3. Streptococcus pneumonia 4. Streptococcus viridans 5. Staphylococcus aureus
6. Coagulase negative staphylococci 7. Proteus mirablis
8. citrobacter
Miscellaneous gram positive and gram negative organisms.
ASCITIC FLUID LACTOFERIN
Measuring ascitic fluid lactoferin, which is a proposed marker of SBP can also be used to detect spontaneous bacterial peritonitis. Normal value: 242 ng/ml. in studies of its usefulness in detecting sbp its values were elevated in thousands indicating the severity of infection and inflammation of asciti fluid.
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TREATMENT FOR SPONTANEOUS BACTERIAL PERITONITIS
DISEASE SEVERITY AND CLINICAL OUTCOME
Studies have shown that the mortality rate due to spontaneous bacterial peritonitis in hospitalized patients in the past was around 80% to 90%.
However, widespread use of diagnostic paracentesis with the higher index of suspicion of infection, with various diagnostic criteria, together with use of better and safer antibiotics, has significantly improved the short-term prognosis in SBP patients. Currently, there are essentially no deaths as a result SBP, provided it is detected and treated before the development of its complications likes shock or renal failure.
Though the prognosis of SBP has improved in recent years with the advent of effective antibiotics and quick intervention, the long-term prognosis
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of SBP remains extremely poor among survivors of an episode of SBP, due to the manifestations of severe impairment of liver function.
Probabilities of survival for 1 and 2 years are in the range of 20% and 30% respectively and in some cases 30 to 50%. Liver transplantation should be considered for patients who survive an episode of SBP
Factors associated with poor outcome include several indicators of poor liver function such as the development of renal failure, hepatic encephalopathy, high levels of serum bilirubin, and upper gastrointestinal bleeding. The development of renal impairment after the diagnosis of SBP is probably the strongest independent predictor of death.
In a study by Follo et al. in 252 consecutive episodes of SBP, the mortality rate was 100% when associated with progressive renal impairment.
NUETROPHIL LYMPHOCYTE RATIO SIGNIFICANCE:
NEUTROPHILS IN THE ASCITIC FLUID
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Sepsis is one of the leading cause of mortality and morbidity worldwide.
Misdiagnosis or delay in diagnosis causes increase in both morbidity and mortality. Studies on improving early diagnosis and treatment have been performed to decrease the mortality rates. Neutrophil-lymphocytic ratio (NLR) is relatively cost effective biological parameter that is easy to calculate from pheripheral blood counts and can also be easily calculated in the body fluids considered to be infected.
Elevated neutrophil-lymphocytic ratio is not only associated with sepsis but also with variety of other conditions such as trauma, surgery, cardiac, rheumatic disorders and pancreatitis etc. An observational cohort study by liu et al published at 2016, that the neutrophil-lymphocytic ratio of the pheripheral blood, of the infected fluid had an independent predictable mortality rate. The changes in the serial values of neutrophil-lymphocytic ratio can be used as a prognostic marker.
As the number of DCLD patients getting admitted in the emergency department are on the rise, with symptoms suggestive of spontaneous bacterial peritonitis and also with other symptoms such as UGI bleed, hepatic encephalopathy, fever, abdominal pain for that more easily accessible tools are required for evaluating these patients. It has been postulated after "N" number of studies, neutrophil-lymphocytic ratio can give directions in the emergency department for treating patients with spontaneous bacterial peritonitis and also other infective etiologies, for the physicians in the emergency room.
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LYMPHOCYTES IN THE ASCITIC FLUID
NUETROPHIL-LYMPHOCYTIC ratio is used as an index of systemic inflammation. NLR along with CRP can reflect the magnitude of inflammation and sepsis accurately. In the setting of limited laboratory and financial facilities, using NLR seems to be a rational approach for the management of patients in sepsis such as spontaneous bacterial peritonitis(both ascitic fluid and of that pheripheral blood), pneumonia , tumours, myocardial infarction, stroke etc..
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MATERIALS AND METHODS
STUDY TYPE
PROSPECTIVE OBSERVATIONAL STUDY.
STUDY PLACE
This study was done in Department of General Medicine, Coimbatore Medical College in association with the Department of Pathology, Department of MGE, Coimbatore medical college hospital, Coimbatore.
STUDY PERIOD
FEBRAURY 2017 to FEBRAURY 2018 STUDY POPULATION
During this period ascitic fluid from 100 cases of cirrhosis attending the Department of General Medicine, Coimbatore Medical College Hospital were examined for Ascitic fluid Infections (AFIs).
A total of 100 patients with ascites with cirrhosis were enrolled in this study. CBC, ESR, LFT, PT, INR, UREA, ASCITIC FLUID TOTAL COUNT, DIFFERENTIAL COUNT FOR % OF NUETROPHILS AND LYMPHOCYTES, ASCITIC FLUID CULTURE to confirm the presence of infection, serum ascitic albumin gradient to confirm the presence of portal hypertension were determined for all participants. The ability of Leukocyte
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esterase reagent strip kit in determining ascitic fluid infections in comparison with NUETROPHIL-LYMPHOCYTIC ratio were analysed using Pearson chi- square and Fisher extract test.
INCLUSION CRITERIA
All inpatients with Decompensated Liver Disease (DCLD), before the first dose of antibiotic administration, above the age of 18 years
In the medical wards and intensive care unit in whom the presence of ascites is confirmed by clinical and ultrasound examination
What ever the etiology may be like alcohol use, hepatitis B, hepatitis C, genetic hemochromatosis, wilsons disease, non alcoholic fatty steato hepatitis, primary biliary cirrhosis, hepato cellular carcinoma, cryptogenic cirrhosis, budd chiari syndrome..etc..
EXCLUSION CRITERIA
Patients who were on antibiotics in the previous two days.
Patients with secondary causes of peritonitis like gut perforation, Peritoneal carcinomatosis, peritoneal tuberculosis
Patients below 18 years of age
Pregnant patients
Patients who underwent surgery in the previous 3 months
Chylous ascites
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Ascites not related to portal hypertension like pancreatic ascites, peritoneal tuberculosis, pancreatic pseudocyst.
ETHICAL CONSIDERATION
Ethical with research clearance was obtained from the Ethical Committee Coimbatore Medical College. Written consent done before enrolment.
INFORMED CONSENT
Written informed consent was obtained from each patient. If patients were unable to provide consent, written consent was obtained from their legal guardians (father, mother, spouse, son or daughter). Patients who were unable to provide consent and were not accompanied by a legal guardian were not enrolled in the study.
STATISTICAL DATA
Statistical data obtained with SPSS Software (Statistical Package for Social Sciences) version 20. Univariate analysis was done using Pearson ChiSquare Test and Fisher’s Exact Test.
SAMPLE COLLECTION
After history taking and physical examination, all patients proved to have portal hypertension and ascites clinically (i.e., presence of ascites and
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splenomegaly) and by bedside ultrasonography, who met the above mentioned criteria during the study period, were cordially involved in the study. Consent forms were provided, and the aim of the study was explained. After obtaining written informed consent, patients were enrolled in the study.
METHODS
PARACENTESIS
PREFERRED SITE FOR PARACENTESIS
Left lower quadrant was taken with two finger breadths cephalad and two finger breadths medial to the anterior superior iliac spine (RUNYON’S SPOT) where the abdominal wall is thinner with larger pool of fluid. Right lower quadrant was not the choice since appendicectomy scar /dilated caecum are present.
The Inferior epigastric arteries and midline (collaterals) were spared.
Visible collaterals were also spared.
POSITION OF THE PATIENT
The head end of the bed elevated . Patients with large volume of ascites and thin abdominal wall were “tapped” in this supine position. Patients with less amount of fluid were placed in the lateral decubitus position and tapped from left lower quadrant.
