Body Fluid Panel
The serous body cavities are mesothelial lined potential spaces surrounding the lungs, heart and abdomen. Normally, they contain a small amount of fluid that is an ultrafiltrate of plasma. The maintenance of body fluids is a dynamic continuous process of formation and resorption. Formation of fluids is through the vascular system, which produces small amounts of ultra-filtrated plasma to lubricate body cavities and synovial joints, and to add bouancy to the central nervous system. Under normal conditions, the amount of fluid is small, but the body cavities represent potentially large spaces where fluid can accumulate. Excessive fluid (effusion) can accumulate if production is increased and/or resorption of fluid is decreased. When production and resorption of this ultrafiltrate are not balanced, fluid may accumulate, resulting in an effusion. Effusions may be classified as transudates or exudates.
Laboratory Evaluation
Excessive fluid can be removed from the body by procedures to provide relief from pressure symptoms, and to provide diagnostic studies.
The appearance of the pleural fluid and any odour should be noted.
Fluid / Suspected diseasePutrid odour / Anaerobic empyema
Food particles / Oesophageal rupture
Bile stained / Cholothorax (biliary fistula)
Milky / Chylothorax/pseudochylothorax
Anchovy sauce” like fluid / Ruptured amoebic absces
· The unpleasant aroma of anaerobic infection may guide antibiotic choice.
· The appearance can be divided into serous, blood tinged, frankly bloody, or purulent.
· Fluid is turbid or milky centrifuge it. Supernatant clear cell debris and empyema is likely.
· If it is still turbid, it is due to high lipid content and a chylothorax or pseudochylothorax are likely.
· If fluid appears bloody, a haematocrit can be obtained if there is doubt as to whether it is a haemothorax.
· If the haematocrit of the pleural fluid is more than half of the patient’s peripheral blood haematocrit, the patient has a haemothorax.
· If the haematocrit on the pleural fluid is less than 1%, the blood in the pleural fluid is not significant.
· Grossly bloody pleural fluid is usually due to malignancy, pulmonary embolus with infarction, trauma, benign asbestos pleural effusions, or post-cardiac injury syndrome (PCIS)
Fluids received in the laboratory often undergo four areas of testing
1) chemistry analysis
2) hematologic cell count and identification
3) microbiological stains and cultures and
4) cytopathologic examination.
The combination of these four areas of testing helps to identify the fluid as a transudate or an exudate, and in many cases provides information about the etiology of the fluid formation
Transudates are usually bilateral and arise from either increased capillary hydrostatic pressure or decreased oncotic pressure secondary to congestive heart failure, fluid overload, cirrhosis or hypoalbuminemia.
Causes of transudative pleural effusions
Very common causes / Less common causes / Rare causes• Left ventricular failure
• Liver cirrhosis
• Hypoalbuminaemia
• Peritoneal dialysis / • Nephrotic syndrome
• Mitral stenosis
• Pulmonary embolism
• Hypothyroidism / • Constrictive pericarditis
• Urinothorax
• Superior vena cava obstruction
• Ovarian hyperstimulation
• Meigs’ syndrome
Exudates are usually unilateral and result from increased capillary permeability or decreased lymphatic resorption associated with infection, connective tissue disease, pancreatitis or cancer.
/Exudates
Causes of exudative pleural effusions
Common causes / Less common causes / Rare causes• Malignancy
• tuberculosis of lung
• Parapneumonic effusions / • Pulmonary infarction
• Rheumatoid arthritis
• Autoimmune diseases
• Benign asbestos effusion
• Pancreatitis
• Post-myocardial infarction syndrome / • Yellow nail syndrome
• Drugs (see box 1)
• Fungal infections
Several laboratory tests are helpful in distinguishing transudates from exudates including pH, total protein, lactate dehydrogenase (LD), amylase, glucose, white cell count and differential. Only one of these values has to fall into the exudate range for the effusion to be classified as an exudate. Large chemistry panels should not be ordered on body fluids.
Light’s criteria have been widely used to classify pleural and pericardial fluid as a transudate or an exudates.
Light’s Criteria
Lab Test / Transudate / ExudateAppearance / clear, pale yellow / turbid, bloody
Fluid total protein / 3.0 g/dL or less / >3.0 g/dL
Fluid/serum protein / <0.5 / >0.5
Fluid/serum LD / <0.6 / >0.6
Fluid LD / <0.67 x ULN serum / >0.67 x ULN serum
Cholesterol / <45 mg/dL / 45 mg/dL or greater
Specific gravity / <1.015 / >1.015
Exudates typically have higher protein concentration and LD activity and lower pH and glucose values than transudates. The protein concentration of an exudate usually exceeds 3 g/dL. Exudate LD activity is greater than 0.67 times the upper limit of normal for serum.
Pleural Effusions
Other tests may also be helpful in evaluating pleural effusions. Pleural fluid pH is useful to evaluate the prognosis of effusions associated with pneumonia. Normal pleural fluid pH is 7.6. A pleural fluid pH >7.3 suggests that resolution is possible with medical therapy alone. A pH < 7.2 suggests that a more complicated effusion or empyema requiring surgical drainage has probably formed. Pleural fluid pH should be measured with a blood gas analyzer and not with litmus paper or a pH meter, because both of the latter methods result in falsely elevated values.
A pleural fluid glucose < 60 mg/dL or a pleural fluid: serum glucose ratio < 0.5 may be seen in effusions caused by cancer, tuberculosis, empyema and rheumatoid arthritis.
Chylous Pleural Effusions
Chylous pleural effusions usually result from disruption or obstruction of the thoracic duct and are typically described as exudative lymphocytic pleural effusions with a milky appearance. Identifying chylothorax is important in determining the etiology of pleural effusion, but the biochemical parameters of chylous effusions have never been thoroughly analyzed. The criteria published in most medical textbooks were based on a small study published more than 30 years ago. Recently, investigators from the Mayo Clinic published their biochemical analysis of the pleural fluid obtained from 74 adults with a diagnosis of chylothorax (Mayo Clin Proc. Feb 2009;84(2)129-33). Gross appearance of the fluid was not a sensitive diagnostic criterion in identifying chylothorax. Only 44% of cases had the classic milky appearance attributed to chylothorax. A nonmilky appearance should not be used as a criterion to rule out a chylous effusion.
Most chylous effusions (86%) were classified as exudative effusions. Only 10% of the chylous effusions had lactate dehydrogenase levels in the exudative range. The traditional biochemical criterion for chylothorax is a pleural fluid triglyceride level greater than 110 mg/dL. The Mayo study validated this criterion. The mean+/-SD triglyceride value for transudative chylothoraces was 192+/-105 with a median of 195 mg/dL while the mean+/-SD triglyceride value for exudative chylothoraces was 855+/-816 with a median of 601 mg/dL. However, 14% of patients had triglyceride values less than 110 mg/dL, primarily due to perioperative fasting and malnourishment.
In cases of suspected chylous effusion with triglycerides less than 110 mg/dL, the specimen can be sent to a reference laboratory for lipoprotein electrophoresis. The presence of chlyomicrons in the fluid supports the diagnosis of chylothorax.
Causes of chylothorax and pseudochylothorax
Chylothorax
Chylothorax / Pseudochylothorax• Neoplasm: lympho ma, metastatic carcinoma
• Trauma: operative, penetrating injuries
• Miscellaneous: tuberculosis, sarcoidosis, lymphangioleiomyomatosis, cirrhosis, obstruction of central veins, amyloidosis / • Tuberculosis
• Rheumatoid arthritis
• Poorly treated empyema
·
Differential cell counts on the pleural fluid
• Pleural lymphocytosis is common in malignancy and tuberculosis.
• Eosinophilic pleural effusions are not always benign.
When polymorphonuclear cells predominate, the patient has an acute process affecting the pleural surfaces. If there is concomitant parenchymal shadowing, the most likely diagnoses are parapneumonic effusion and pulmonary embolism with infarction.
If there is no parenchymal shadowing, more frequent diagnoses are pulmonary embolism, viral infection, acute tuberculosis, or benign asbestos pleural effusion.
Eosinophilic pleural effusion is defined as the presence of 10% or more eosinophils in the pleural fluid. The presence of pleural fluid eosinophilia is of little use in the differential diagnosis of pleural effusions. Benign aetiologies include parapneumonic effusions, tuberculosis, drug induced pleurisy,benign asbestos pleural effusions, Churg-Strauss syndrome, pulmonary infarction, and parasitic disease.18–20 It is often the result of air or blood in the pleural cavity.19 However, malignancy is also a common cause; 11 of a series of 45 eosinophilic effusions were due to cancer.20
If the pleural fluid differential cell count shows a predominant lymphocytosis, the most likely diagnoses are tuberculosis and malignancy. Although high lymphocyte counts in pleural fluid raise the possibility of tuberculous pleurisy,9 as many as 10% of tuberculous pleural effusions are predominantly neutrophilic.21 Lymphoma, sarcoidosis, rheumatoid disease, and chylothorax can cause a lymphocytic pleural effusion.22
Coronary artery bypass grafting (CABG) often causes pleural effusions which can usually be treated conservatively.
Large symptomatic effusions can occur in up to 1% of patients in the postoperative period. These are predominantly left sided and the differential cell count can help to clarify the situation.
Bloody effusions are usually eosinophilic, occur early, and are related to bleeding into the pleural cavity from the time of surgery.
Non-bloody effusions tend to have small lymphocytes as their predominant cell type, occur later, and are generally more difficult to treat.
• pH should be performed in all non-purulent effusions.[B]
• In an infected effusion a pH of <7.2 indicates the need for tube drainage. [B]
A pleural fluid pH of <7.2 with a normal blood pH is found in the same diagnoses as a low pleural fluid glucose.24 A pH of <7.2 represents a substantial accumulation of hydrogen ions, as normal pleural pH is about 7.6 because of bicarbonate accumulation in the pleural cavity. The main clinical use for the measurement of pleural pH is the identification of pleural infection.25 26 This is covered in detail in the guideline on pleural infection (page ii18). Other diseases causing an exudative pleural effusion with a low pH are collagen vascular diseases (particularly rheumatoid arthritis),oesophageal rupture, and malignancy.24
A prospective study of the value of pH in malignant pleural effusions by Rodriguez and Lopez27 in 77 patients undergoing thoracoscopy showed that a pH of <7.3 was associated with more extensive malignancy, a 90% chance of positive cytology,and a 50% chance of failed pleurodesis. Sahn and Goodshowed that a reduced pH (<7.3) predicted poor survival in malignant pleural disease (pH >7.3, median survival 9.8 months; pH <7.3, survival 2.1 months).28
5.5 Glucose
A pleural glucose level of less than 3.3 mmol/l is found in exudative pleural effusions secondary to empyema, rheumatoid disease, lupus, tuberculosis, malignancy, or oesophageal rupture.29 The lowest glucose concentrations are found in rheumatoid effusions and empyema.29–32 In pleural infection, pH discriminates better than glucose.26 33 Rheumatoid arthritis is unlikely to be the cause of an effusion if the glucose level in the fluid is above 1.6 mmol/l (see section 8.6.1).30
5.6 Amylase
• Amylase measurement should be requested if acute pancreatitis or rupture of the oesophagus is possible.[C]
• Iso-enzyme analysis is useful in differentiating high amylase levels secondary to malignancy or ruptured oesophagus from those raised in association with abdominal pathology.
Pleural fluid amylase levels can be useful in the evaluation of an exudative effusion. Pleural fluid amylase levels are elevated if they are higher than the upper limits of normal for serum or the pleural fluid/serum ratio is >1.0.31 This suggests acute pancreatitis, pancreatic pseudocyst, rupture of the oesophagus, ruptured ectopic pregnancy, or pleural malignancy (especially adenocarcinoma).9 Approximately 10% of malignant effusions have raised pleural amylase levels.34
Iso-enzyme analysis can be useful in suspected cases of oesophageal rupture as this will show the amylase is of salivary origin.35 If the salivary amylase is raised and oesophageal rupture is not suspected, malignancy is most likely. Pleural effusions associated with pancreatic disease usually
contain pancreatic amylase.36
In a prospective study of 176 patients, 10 had an amylase rich effusion. Of these, four had pancreatitis which had not previously been suspected. The rest were due to nonpancreatic diseases of which lung cancer was predominant.37
The incidence of pleural effusion with acute pancreatitis exceeds 50%. Patients with acute pancreatitis and a pleural effusion tend to have more severe disease and a higher likelihood of subsequently developing a pseudocyst than those without effusions.38
5.7 Cytology
• Malignant effusions can be diagnosed by pleural fluid cytology alone in only 60% of cases.
• If the first pleural cytology specimen is negative, this should be repeated a second time. [B]
• Both cell blocks and fluid smears should be prepared for examination and, if the fluid has clotted, it needs to be fixed and sectioned as a histological section. [B]
Peritoneal Fluid
The criteria for classifying transudates and exudates in pleural and pericardial fluids are often misleading when applied to peritoneal fluid (ascites). Transudative processes may produce a peritoneal fluid protein level in the exudate range. Calculation of a serum to ascites albumin gradient (SAAG) is a more physiologically appropriate test. It is calculated as the serum albumin concentration minus the peritoneal fluid albumin.
SAAG = (albuminconcentration ofserum) - (albumin concentration of ascitic fluid).
Ideally, the two values should be measured at the same time.
High gradient
A high gradient (> 1.1 g/dL) indicates the ascites is due toportal hypertensionwith 97% accuracy.This is due to increasedhydrostatic pressurewithin the blood vessels of thehepatic portal system, which in turn forces water out into theperitoneal cavitybut leaves proteins such as albumin within the vasculature.
Important causes of high SAAG ascites (> 1.1 g/dL) include:
§ high protein (>2.5):heart failure
§ low protein (<2.5):cirrhosis of the liver,Budd Chiari syndrome
Low gradient
A low gradient (< 1.1 g/dL) indicates ascites not associated with increased portal pressure, includingnephrotic syndrome,tuberculosis, and various types ofcancer
Ascites fluid with an amylase level more than 3 times the serum value is usually caused by pancreatitis, pancreatic pseudocyst or trauma.
Elevated bilirubin may indicate biliary tract injury.
Elevated cholesterol in ascites fluid has been associated with malignancy.